Synthesis of functionalized biphenyl-C-nucleosides and their incorporation into oligodeoxynucleotides

Article abstract of DOI:10.1016/j.bmc.2006.05.072

We describe the synthesis of eight novel C-nucleosides in which the nucleobases are replaced by biphenyl residues that carry one or two electron donor (-OCH₃, -NH₂) or acceptor (-NO₂) functional groups in the distal ring. These C-nucleosides were synthesized convergently and in high yields from a common bromophenyl-C-nucleoside precursor via Suzuki coupling with the respective boronic acids or esters. These nucleosides were subsequently converted into the corresponding phosphoramidite building blocks and efficiently incorporated into oligodeoxynucleotides by standard phosphoramidite chemistry.

Full text of DOI:10.1016/j.bmc.2006.05.072

Bioorganic & Medicinal Chemistry 14 (2006) 6174–6188
Synthesis of functionalized biphenyl-C-nucleosides
and their incorporation into oligodeoxynucleotides
Alain Zahn and Christian J. Leumann*
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland
Received 24 March 2006; accepted 30 May 2006
Available online 19 June 2006
Dedicated to Bernd Giese in appreciation of his creative contributions to radical chemistry.
Abstract—We describe the synthesis of eight novel C-nucleosides in which the nucleobases are replaced by biphenyl residues that
carry one or two electron donor (–OCH3,–NH2) or acceptor (–NO2) functional groups in the distal ring. These C-nucleosides were
synthesized convergently and in high yields from a common bromophenyl-C-nucleoside precursor via Suzuki coupling with the
respective boronic acids or esters. These nucleosides were subsequently converted into the corresponding phosphoramidite building
blocks and efficiently incorporated into oligodeoxynucleotides by standard phosphoramidite chemistry.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
through the corresponding base stack,7 we set out to
prepare a series of biphenyl C-nucleosides with elec-
tron-donating or electron-withdrawing groups in the
distal phenyl ring. Here, we describe the synthesis and
the incorporation into oligodeoxynucleotides of a series
of novel, methoxy, nitro- or amino-modified biphenyl-
C-nucleosides.
C-nucleosides are a class of compounds characterized by
the replacement of the acid labile C–N glycosidic bond
by a stable C–C bond. Many of them possess antiviral
and antineoplastic activities and are thus of interest in
medicinal chemistry.1 In the context of nucleic acids,
C-nucleosides bearing simple aromatic groups as nucle-
obase surrogates have recently been of interest to deter-
mine the energetic contribution of base-stacking to
double helix stability,2 to determine complementary
base insertion fidelity of DNA polymerases,3 as tools
in DNA-based diagnostics,4 and as novel orthogonal
DNA base-pairs for the extension of the genetic
alphabet.5
2. Results and discussion
In our synthesis we followed a highly convergent strate-
gy starting from a common phenyl C-nucleoside precur-
sor, to which the modified second phenyl ring is
introduced via Suzuki coupling with suitably substituted
phenyl-boronic acids or esters. Parallel to our work, Ho-
cek et al. worked out a similar synthesis to access differ-
ent biarylic nucleosides.8 The advantage of our synthesis
is the diastereoselective access to the intermediate for
Suzuki coupling. The drawback of both strategies is
the relatively poor yield in the glycosidic bond forma-
tion reaction leading to the respective intermediates.
In our own research directed to exploit interstrand aro-
matic interactions for producing novel and functional
DNA duplex architectures we recently found that up
to seven biphenyl C-nucleotide-pairs can be accommo-
dated in the center of a helix without breakdown of
duplex stability.6 To investigate the influence of the
p-electron density of the biphenyl residues on duplex
stability and on electron or charge transport properties
The synthesis of key-intermediate 3b followed estab-
lished routes in C-glycoside chemistry (Scheme 1). 20-de-
oxy-ribonolactone 2 was synthesized starting from
20-deoxy-D-ribose following a protocol by Woski.9 Oxi-
dation with bromine in water10 followed by protection
with tert-butyldimethylchlorosilane (TBS-Cl) in the
presence of imidazole in DMF11 afforded the
Keywords: Nucleoside analogues; Biphenyls; Suzuki coupling;
Oligonucleotides.
*
Corresponding author. Tel.: +41 031 631 4355; fax: +41 031 631
3422; e-mail: leumann@ioc.unibe.ch
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.05.072

A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
6175
Br
O
O
O
OH
O
a,b
HO
TBSO
TBSO
RO
c,d
88%
19%
HO
RO
1
2
e
75%
3a: R = TBS
3b: R = H
g
78%
f
3c: R = Ac
3d: R = THP
99%
Scheme 1. Reagents and conditions: (a) Br2, H2O, rt, 5 d; (b) TBS-Cl, imidazole, DMF, rt, 16 h; (c) 1,4-dibromo-benzene, n-BuLi, THF, ꢀ78 ꢁC,
30 min, then 2 in THF, ꢀ78 ꢁC, 1 h; (d) Et3SiH, BF3ÆOEt2, CH2Cl2, ꢀ78 ꢁC, 6 h; (e) TBAF, AcOH, THF, ꢀ10ꢁ ! rt, 16 h; (f) Ac2O, DMAP,
pyridine, rt, 16 h; (g) DHP, Tos-OH, THF, rt, 16 h.
20-deoxy-D-ribonolactone 2 in good yield. Lithiation of
1,4-dibromo-benzene with n-BuLi followed by the addi-
tion to lactone 2 resulted in the intermediate formation
of the corresponding hemiacetals which, upon reduction
with Et3SiH in the presence of a strong Lewis acid
(BF3ÆEt2O), afforded the protected bromophenyl nucleo-
side 3a, although in relatively poor yield. Only the b-an-
omer is formed (confirmed by 1H NMR-NOE-
spectroscopy). TBS-nucleoside 3a was deprotected using
standard conditions and leads to C-nucleoside 3b. To
enhance solubility and to simplify purification after Su-
zuki coupling, compound 3b was protected with acetate
or THP to yield 3c and 3d, respectively.
lower compared to the results obtained with the Buch-
wald method.
To have access to the amino biphenyl C-nucleosides, the
THP-protected nitro-biphenyl-compounds 4g and 4h
were converted to the Fmoc-amino-derivatives 5a and
5b using catalytic hydrogenation followed by Fmoc-pro-
tection14 (Table 2). Deprotection of acetyl or THP,
respectively, followed by standard tritylation and forma-
tion of the phosphoramidite lead to compounds 6a–h in
high yields (Table 3).
Automated oligodeoxynucleotide synthesis was per-
formed on a 1 lmol scale on a DNA synthesizer using
commercially available deoxynucleoside phosphorami-
dites and solid supports. A standard synthesis cycle with
conventional detritylation, oxidation, and capping re-
agents was used. 5-(ethylthio)-1H-tetrazole (0.2 M in
CH3CN) was used as activator. Phosphoramidites 4a–f
were coupled as 0.1 M solutions in CH3CN for 6 min.
Coupling efficiency for the modified phosphoramidites
was >95% as judged from trityl assay. Oligonucleotides
were deprotected and detached from solid support by
standard procedures (concd. NH3, 55 ꢁC, 16 h), purified
by RP-HPLC, and characterized by ESIꢀ mass
For the Suzuki coupling (Table 1) with the commercially
available and suitably substituted phenyl-boronic acids,
the mild conditions of Buchwald12 were employed which
yielded the biphenylic nucleosides 4c–f and 4h in high
yield. This method is very effective already at room tem-
perature and provides excellent results independent of
the electronic properties of the substituents in the aryl-
boronic acids. If the desired phenyl-boronic acid was
not available, the corresponding phenyl-pinacolboro-
nate13 was synthesized and coupled classically using
Pd(PPh3)4 in DMF at 85 ꢁC. In this case, the yields were
Table 1. Conditions for biaryl bond formation (Suzuki coupling)
S1
S2
S2
S1
S3
S3
3b-d
+
O
RO
M
4a-h
RO
Entry
Starting material
S1
S2
H
S3
Ma
Exp. cond.b
Prod.
R
Yield (%)
1
2
3
4
5
6
7
8
3b
3b
3c
3c
3c
3c
3b
3d
NO2
H
NO2
H
Bpin
Bpin
i,ii
i,ii
iv
4a
4b
4c
4d
4e
4f
Ac
Ac
41
82
94
95
93
97
65
80
NO2
H
OMe
H
H
B(OH)2
B(OH)2
B(OH)2
B(OH)2
Bpin
Ac
Ac
OMe
OMe
H
H
iv
OMe
NO2
H
H
iv
Ac
Ac
H
iv
NO2
H
H
i,iii
iv
4g
4h
THP
THP
NO2
H
B(OH)2
a Bpin: pinacolboronate.
b (i) Pd(PPh3)4, K3PO4, DMF, 85 ꢁC, 16 h; (ii) Ac2O, DMAP, pyridine, rt, 16 h; (iii) DHP, Tos-OH, rt, 16 h; (iv) Pd(OAc)2, 2-(di-tert-butyl-
phosphino)-biphenyl, KF, THF, rt, 16 h.

6176
A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
Table 2. Synthesis of aminobiphenyl nucleosides
S1
S1
S2
S3
S2
S3
1.
Pd/C,H2
O
O
2. Fmoc-Cl,
Hünig's base
THPO
THPO
THPO
4g,h
5a,b
THPO
Entry
Starting material
S1
S2
S3
Prod.
S1
S2
S3
Yield (%)
1
2
4g
4h
H
NO2
NO2
H
H
H
5a
5b
H
NHFmoc
NHFmoc
H
H
H
67
64
Table 3. Synthesis of phosphoramidites
S1
S1
1. O-deprotection(6a-h)
2. tritylation(7a-h)
S2
S2
3. phosphitylation
S3
S3
O
O
RO
DMTO
4a-f
5a,b
8a-h
RO
O
P
N
O
CN
Entry
Starting material
S1
S2
S3
R
Exp. cond.a
Prod.
Yieldb (%)
1
1
1
1
1
1
1
1
4a
4b
4c
4d
4e
4f
NO2
H
H
NO2
H
Ac
Ac
i,ii,iii
i,ii,iv
i,ii,iv
i,ii,iv
i,ii,iv
i,ii,iv
v,ii,iv
v,ii,iii
8a
8b
8c
8d
8e
8f
70
65
73
54
70
70
48
75
NO2
H
OMe
H
H
Ac
Ac
OMe
OMe
H
H
OMe
NO2
H
H
Ac
Ac
H
5a
5b
NHFmoc
H
H
THP
THP
8g
8h
NHFmoc
H
a (i) K2CO3, MeOH/CH2Cl2, rt, 16 h; (ii) DMT-Cl, pyridine, rt, 4 h; (iii) N,N,N0,N0-tetraisopropyl-phosphordiamidite, diisopropylammonium-1H-
tetrazo-1-ide, CH2Cl2, rt, 16 h; (iv) CEP-Cl, THF, rt, 2 h; (v) Tos-OH, MeOH/CH2Cl2, rt, 16 h.
b Over three steps.
spectrometry. In this way we prepared the 18 oligode-
oxynucleotides listed in Table 4. In all cases we isolated
the oligonucleotides in good yields and found the mea-
sured masses to match with the expected molecular
weight.
transport properties are currently underway and will be
reported in due time.
4. Experimental
4.1. General
3. Conclusions
All reactions were performed in dried glassware under
argon. All chemicals were purchased from commercial
suppliers (Fluka, Aldrich) and were used without further
purification. Solvents for reactions were dried and puri-
fied by filtration over alumina (THF, Et2O, CH2Cl2 and
toluene), distilled over CaH2 (pyridine, CH3CN) or pur-
chased as crown-cap bottles from Fluka (DMF, diox-
ane, pyridine and CH3CN). Solvents for extractions
and FC were distilled before use. Silica gel thin layer
chromatography was performed using SIL G-25
UV254 plates from Macherey-Nagel. Visualization was
done using UV-light (254 nm) or staining solutions
We have developed a short and highly convergent syn-
thesis of a series of novel biphenyl C-nucleosides with
electron withdrawing or electron donating functional
groups in the distal phenyl ring based on the Suzuki
coupling for biarylic bond formation. These C-nucleo-
sides were easily converted into the corresponding
phosphoramidite building blocks for DNA synthesis
and incorporated into oligodeoxynucleotides by stan-
dard phosphoramidite chemistry. Experiments toward
the determination of the pairing properties of these
modified oligonucleotides as well as toward their charge

A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
6177
Table 4. Sequence and analytical data as well as isolated yields (OD260) of oligonucleotides prepared
OMe
OMe
NO2
NO2
OMe
NO2
O
O
O
O
RO
RO
RO
RO
X2
X3
X4
X1
RO
RO
RO
RO
Sequence
Mass calcd [MꢀH]ꢀ
Mass found [MꢀH]ꢀ
OD260
50-GTGACX4GCAG-30
50-CTGCX3GTCAC-30
3185.15
3066.15
3757.52
3668.45
3742.54
3653.48
3772.57
3683.51
3802.51
3713.45
4512.14
4423.08
4467.23
4378.17
4557.31
4468.25
4647.14
4558.07
3185.60
3065.72
3757.00
3668.13
3742.13
3653.13
3772.38
3683.50
3802.50
3714.13
4512.25
4423.00
4467.25
4378.13
4557.50
4468.38
4647.38
4558.13
43.4
43.6
54.2
52.0
70.2
52.8
65.3
59.8
57.3
48.7
34.9
22.7
23.8
24.0
36.0
26.0
17.4
24.1
50-GATGACX1GCTAG-30
50-CTAGCX1GTCATC-30
50-GATGACX2GCTAG-30
50-CTAGCX2GTCATC-30
50-GATGACX3GCTAG-30
50-CTAGCX3GTCATC-30
50-GATGACX4GCTAG-30
50-CTAGCX4GTCATC-30
50-GATGACX1X1X1GCTAG-30
50-CTAGCX1X1X1GTCATC-30
50-GATGACX2X2X2GCTAG-30
50-CTAGCX2X2X2GTCATC-30
50-GATGACX3X3X3GCTAG-30
50-CTAGCX3X3X3GTCATC-30
50-GATGACX4X4X4GCTAG-30
50-CTAGCX4X4X4GTCATC-30
(either 2.1 g cerium(IV) sulfate, 4.2 g phosphomolybdic
acid, 12 ml H2SO4, and 180 ml H2O or 10 ml p-anisalde-
hyde, 2 ml acetic acid, 10 ml H2SO4, and 180 ml EtOH).
Flash chromatography (FC) was performed with silica
gel 60 A (particle size 40–63 lm). 1H NMR spectra were
recorded at 300 MHz on a Bruker Avance, or at
400 MHz on a Bruker DRX-400 spectrometer. Chemi-
cal shifts are reported in ppm relative to tetramethylsi-
lane (TMS) as internal standard. Coupling constants J
are in Hz. Multiplicities are abbreviated as follows:
s = singlet, d = doublet, t = triplet, m = multiplet, and
br = broad. 13C NMR spectra were recorded at
75 MHz on a Bruker Avance, or at 101 MHz on a Bru-
ker DRX-400 spectrometer. Chemical shifts are report-
ed in ppm relative to TMS. Multiplicities are
established by DEPT experiments and are abbreviated
as follows: s = singlet, d = doublet, t = triplet, q = qua-
4.1.1. 3,5-Bis-O-(tert-butyldimethylsilyl)-2-deoxy-D-rib-
ono-1,4-lactone (2). A solution of 20-deoxy-D-ribose (1,
5 g, 37.3 mmol) and Br2 (4.8 ml, 93.4 mmol) in H2O
(125 ml) was stirred for 5 d in the dark. The excess of
bromine was removed in vacuo and the solution was
neutralized with Ag2CO3. The mixture was filtered
through Celite and concentrated in vacuo. The residue
was dissolved in dry DMF (100 ml) and cooled to
0 ꢁC. Imidazole (12.7 g, 186.5 mmol) and tert-butyldim-
ethylchlorosilane (13.6 g, 90.2 mmol) were added and
the solution was allowed to warm up to room tempera-
ture and was stirred for 16 h. The solution was poured
into water (300 ml) and extracted with t-BuOMe
(4 ·150 ml). The combined organic phases were washed
with satd. NaHCO3 solution (100 ml), water (100 ml),
and brine (100 ml), dried (MgSO4), filtered, and concen-
trated in vacuo. Purification by FC (silica gel; CH2Cl2)
yielded the desired compound 2 (11.9 g, 33.0 mmol,
1
1
druplet, and m = multiplet. H/1H and H/13C correla-
tion experiments (COSY, HMSC) were used for signal
assignments. 31P NMR spectra were recorded at
162 MHz on a Bruker DRX-400 spectrometer using
1
88%) as colorless crystals. Rf 0.5 (CH2Cl2). H NMR
(300 MHz, CDCl3): d 4.54–4.48 (m, 1H, H-C(40));
4.36–4.32 (m, 1H, H-C(30)); 3.72–3.86 (m, 2H, H-
C(50)); 2.82 (dd, 1H, J1 = 6.6, J2 = 17.7, H-C(20)); 2.39
(dd, 1H, J1 = 2.6, J2 = 17.6, H-C(20)); 0.89 (s, 18H, 2·
C(CH3)3); 0.09 (s, 12H, 4· Si–CH3). 13C NMR
(75 MHz, CDCl3): d 175.75 (s, C(10)); 88.08 (d, C(40));
69.58 (d, C(30)); 62.43 (t, C(50)); 39.00 (t, C(20)); 25.77,
25.62 (2q, 2· C(CH3)3); 18.21, 17.89 (2s, 2· C(CH3)3);
ꢀ4.78, ꢀ4.86, ꢀ5.55, ꢀ5.67 (4q, 4· Si–CH3). ESI+-MS
(CH3CN): m/z 361 ([M+H]+). IR (KBr): tmax 2958s,
2931s, 2888m, 2858s, 1772s, 1472m, 1391m, 1378m,
1362m, 1261s, 1172s, 1127s, 1094s, 1081s, 1008s, 969s,
944s, 916w, 863s, 839s, 781s, 754m, 722w, 687w, 666m,
601w, 540w.
1
85% H3PO4 as an external standard. H NMR-NOE
experiments were recorded on a Bruker DRX-400 spec-
trometer. Electron impact mass spectra (EI-MS) were
recorded on a AutoSpeq Q VG with an ionization ener-
gy of 70 eV. Electrospray ionization mass spectra (ESI-
MS) were recorded either on a Fisons Instrument VG
Platform (low resolution) or on an Applied Biosystems,
Sciex QSTAR Pulsar (high resolution). IR-spectra were
recorded on a Perkin-Elmer Spectrum One. The absorp-
tion maxima (tmax) are indicated in cmꢀ1. The intensities
are abbreviated as follows: s (strong), m (medium), w
(weak), and br (broad).

6178
A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
4.1.2. 4-(30,50-O-(tert-butyldimethylsilyl)-20-deoxy-b-D-
ribofuranosyl)-1-bromobenzene (3a). To a stirred solu-
tion of p-dibromobenzene (12.5 g, 53.2 mmol) in dry
THF (125 ml) at ꢀ78 ꢁC, n-BuLi (1.6 M in hexane,
32 ml, 51.2 mmol) was added fast. After 0.5 h at
ꢀ78 ꢁC, a solution of 2 (11.5 g, 31.89 mmol) in dry
THF (125 ml) was slowly added. The solution was stir-
red for 1 h at ꢀ78 ꢁC and then quenched with sat.
NH4Cl solution (200 ml). The mixture was extracted
with CH2Cl2 (4 · 150 ml). The combined organic phases
were washed with sat. NH4Cl solution (100 ml), H2O
(100 ml), and brine (100 ml), dried (MgSO4), and con-
centrated in vacuo. The yellow residue was dissolved
in dry CH2Cl2 (125 ml) and the solution was cooled to
ꢀ78 ꢁC. Triethylsilane (15.2 ml, 95.6 mmol) followed
by BF3ÆOEt2 (12.1 ml, 95.8 mmol) was added dropwise.
The solution was stirred at ꢀ78 ꢁC for 6 h and then
quenched with sat. NaHCO3 solution (200 ml). The mix-
ture was extracted with CH2Cl2 (4 · 150 ml). The com-
bined organic phases were washed with sat. NaHCO3
solution (100 ml), H2O (100 ml), and brine (100 ml),
dried (MgSO4), and concentrated in vacuo. Purification
by FC (silica gel; toluene) yielded the desired compound
3a (3.03 g, 6.0 mmol, 19%, b-anomer only) as a slightly
yellow oil. Rf 0.5 (Toluene). 1H NMR (400 MHz,
CDCl3,): d 7.44 (d, J = 8.6, 2H, H(arom)); 7.26 (d, 2H,
J = 8.6, H(arom)); 5.10 (dd, 1H, J1 = 5.4, J2 = 10.3, H-
C(10)); 3.99–3.94 (m, 1H, H-C(30)); 3.79–3.74 (m, 1H,
H-C(40)); 3.77 (dd, 1H, J1 = 3.7, J2 = 10.8, H-C(50));
3.33 (dd, 1H, J1 = 5.6, J2 = 10.8, H-C(50)); 2.11 (ddd,
1H, J1 = 1.5, J2 = 5.4, J3 = 12.6, Ha-C(20)); 1.89–1.81
(m, 1H, Hb-C(20)); 0.92, 0.91 (2s, 18H, 2· C(CH3)3);
0.10, 0.09 (2s, 12H, 4· Si–CH3). 13C NMR (75 MHz,
CDCl3): d 141.53 (s, C(arom)); 131.28, 127.74 (2d,
C(arom)); 121.01 (s, C(arom)); 88.14 (d, C(40)); 79.43
(d, C(10)); 74.31 (d, C(30)); 63.76 (t, C(50)); 44.40 (t,
C(20)); 25.90, 25.81 (2q, 2· C(CH3)3); 18.33, 18.03 (2s,
2· C(CH3)3); ꢀ4.66, ꢀ4.69, ꢀ5.40, ꢀ5.48 (4q, 4· Si–
CH3). Difference-NOE: 5.10 (H-C(10)) ! 3.79–3.74
(H-C(40), 3%), 2.11 (H-C(20), 5%); 3.99–3.94 (H-
C(30)) ! 3.74 (H-C(40), 4%), 1.89–1.81 (H-C(20), 5%);
3.74 (H-C(40)) ! 5.10 (H-C(10), 3%), 3.99–3.94 (H-
C(30), 3%), 3.77 (H-C(50), 4%). HR-ESI+-MS: m/z
(ddd, 1H, J1 = 1.5, J2 = 5.3, J3 = 12.6, H-C(20)); 1.77–
1.65 (m, 1H, H-C(20)). 13C NMR (101 MHz, DMSO-
d6): d 142.45 (s, C(arom)); 131.17, 128.37 (2d, C(arom));
120.24 (s, C(arom)); 88.07 (d, C(40)); 78.70 (d, C(10));
72.56 (d, C(30)); 62.56 (t, C(50)); 43.79 (t, C(20)). HR-
EI-MS: m/z 272.0049 (M+; C11H13BrO3 calcd
272.0048). IR (KBr): tmax 3393br, 2896m, 1593w,
1491m, 1441w, 1412m, 1336m, 1263w, 1213w, 1181w,
1061s, 1044s, 1011m, 998s, 972m, 946m, 920w, 893w,
875w, 821s, 748w, 694w, 595w, 536w, 503w, 473w.
4.1.4. 4-(30,50-O-Acetyl-20-deoxy-b-D-ribofuranosyl)-1-
bromo-benzene (3c). To a solution of 3b (100 mg,
0.37 mmol) and DMAP (9 mg, 0.07 mmol) in dry pyri-
dine (2.2 ml) at 0 ꢁC, Ac2O (90 ll, 0.95 mmol) was add-
ed dropwise. The mixture was stirred at room
temperature over 16 h and then diluted with CH2Cl2
(50 ml). The mixture was washed with water (25 ml)
and brine (25 ml), and the combined aqueous phases
were extracted with CH2Cl2 (3 · 25 ml). The combined
organic phases were dried (MgSO4), filtered, and con-
centrated in vacuo. The residue was co-evaporated with
toluene (2 · 5 ml). Purification by FC (silica gel, hexane/
EtOAc 7:3) yielded the desired compound 3c (130 mg,
0.36 mmol, 99%) as a colorless oil. Rf 0.4 (hexane/
1
EtOAc 7:3). H NMR (300 MHz, CDCl3): d 7.48 (d,
2H, J = 8.5, H-C(2), H-C(6)); 7.22 (d, 2H, J = 8.1, H-
C(3), H-C(5)); 5.22 (d, 1H, J = 6.2, H-C(30)); 5.07 (dd,
1H, J1 = 5.1; J2 = 10.7, H-C(10)); 4.38 (dd, 1H,
J1 = 5.7, J2 = 13.1, H-C(50)); 4.29–4.21 (m, 2H,
H-C(40), H-C(50)); 2.34 (ddd, 1H, J1 = 0.8; J2 = 5.2;
J3 = 13.8, H-C(20)); 2.12, 2.08 (2s, 6H, 2· CH3); 2.10–
1.94 (m, 1H, H-C(20)). 13C NMR (101 MHz, CDCl3):
d 170.66, 170.51 (2s, 2· C@O); 139.76 (s, C(4)); 131.63
(d, C(3), C(5)); 127.47 (d, C(2), C(6)); 121.67 (s, C(1));
82.77 (d, C(40)); 79.96 (d, C(10)); 76.55 (d, C(30)); 64.32
(t, H-C(50)); 41.27 (t, H-C(20)); 21.08, 20.84 (2q;
2· CH3). HR-EI-MS: m/z 356.0260 (M+; C15H17BrO5
calcd 356.0259). IR (neat): tmax 1736s, 1488w, 1434w,
1364w, 1223s, 1177w, 1094w, 1052m, 1009m, 946w,
864w, 817m, 687w, 631w, 605w.
4.1.5. 4-[30,50-O-(2-Tetrahydro-2H-pyranyl)-20-deoxy-b-
D-ribofuranosyl]-1-bromobenzene (3d). To a solution of
3b (300 mg, 1.1 mmol) and TsOH (42 mg, 0.22 mmol)
in dry THF (5 ml), 3,4-dihydro-2H-pyran (300 ll,
3.3 mmol) was added dropwise at 0 ꢁC. The mixture
was stirred at room temperature for 16 h and then dilut-
ed with t-BuOMe (100 ml). The mixture was washed
with sat. NaHCO3 solution (50 ml), water (50 ml), and
brine (50 ml), and the combined aqueous phases were
extracted with t-BuOMe (3 · 25 ml). The combined
organic phases were dried (MgSO4), filtered, and con-
centrated in vacuo. Purification by FC (silica gel, hex-
ane/EtOAc 9:1) yielded the desired compound 3d
(381 mg, 0.86 mmol, 78%) as a colorless oil. Rf 0.3 (hex-
ane/EtOAc 9:1). 1H NMR (300 MHz, CDCl3): d 7.44 (d,
2H, J = 8.5, H-C(arom)); 7.31–7.23 (m, 2H, H-
C(arom)); 5.14–5.01 (m, 1H, H-C(100)); 4.74–4.64 (m,
2H, H-THP); 4.48–4.16 (m, 2H, H-C(300), H-C(400));
4.00–3.79 (m, 3H, H-C(500), H-THP); 3.64–3.47 (m,
3H, H-C(500), H-THP); 2.51–2.21 (m, 1H, H-C(200));
2.04–1.46 (m, 13H, H-C(200), H-THP). 13C NMR
523.1687
([M+Na]+;
C23H41BrO3Si2Na
calcd
523.1675). IR (KBr): tmax 2959m, 2931m, 2898w,
2859m, 1490w, 1473w, 1390w, 1362w, 1257m, 1172w,
1092m, 1032w, 1012m, 971w, 939w, 837s, 777m, 666w.
4.1.3.
4-(20-Deoxy-b-D-ribofuranosyl)-1-bromobenzene
(3b). To a solution of 3a (3.0 g, 5.98 mmol) in dry
THF (120 ml) at ꢀ10 ꢁC, acetic acid (350 ll, 6.1 mmol)
and TBAF (5.7 g, 18.07 mmol) were added. After
5 min, the solution was allowed to warm up to room
temperature. After 16 h, the solution was concentrated
in vacuo. Purification by FC (silica gel; CH2Cl2/MeOH
19:1) yielded the desired compound 3b (1.23 g,
4.5 mmol, 75%) as colorless crystals. Rf 0.3 (CH2Cl2/
1
MeOH 19:1). H NMR (300 MHz, DMSO-d6): d 7.50
(d, J = 8.5, 2H, H(arom)); 7.31 (d, 2H, J = 8.1,
H(arom)); 5.07 (d, 1H, J = 3.6, HO-C(30)); 4.97 (dd,
1H, J1 = 5.5, J2 = 10.5, H-C(10)); 4.76 (t, 1H, J = 5.5,
HO-C(50)); 4.20–4.13 (m, 1H, H-C(30)); 3.80–3.74 (m,
1H, H-C(40)); 3.52–3.35 (m, 2H, 2· H-C(50)); 2.06

A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
6179
(75 MHz, CDCl3):
d
141.36, 141.28, 141.24 (3s,
4.2.1. 40-(300,500-Di-O-acetyl-200-deoxy-b-D-ribofuranosyl)-
3,5-dinitrobiphenyl (4a). Method C. Slightly yellow foam
(134 mg, 0.3 mmol, 41%). Rf 0.3 (hexane/EtOAc 7:3). 1H
NMR (300 MHz, CDCl3): d 9.02 (t, 1H, J = 2.1,
H-C(arom)); 8.76 (d, 2H, J = 2.1, H-C(arom)); 7.69 (d,
2H, J = 8.3, H-C(arom)); 7.55 (d, 2H, J = 8.1,
H-C(arom)); 5.27 (d, 1H, J = 6.2, H-C(300)); 5.21 (dd,
1H, J1 = 5.1, J2 = 10.9, H-C(100)); 4.42 (dd, 1H,
J1 = 5.5, J2 = 13.0, H-C(500)); 4.33–4.26 (m, 2H, H-C(400),
H-C(500)); 2.43 (ddd, 1H, J1 = 1.1, J2 = 5.2, J3 = 13.7,
H-C(200)); 2.15, 2.11 (2s, 6H, 2· CH3); 2.15–2.02 (m,
1H, H-C(200)). 13C NMR (101 MHz, CDCl3): d 170.67,
170.55 (2s, 2· C@O); 149.02, 144.42, 142.90, 135.91
(4s, C(arom)); 127.41, 127.00, 126.82, 117.17 (4d,
C(arom)); 82.90 (d, C(400)); 79.99 (d, C(100)); 76.54 (d,
C(300)); 64.32 (t, C(500)); 41.37 (t, C(200)); 21.10, 20.89
(2q, CH3). HR-EI-MS: m/z 444.1170 (M+;
C21H20N2O9 calcd 444.1169). IR (neat): tmax 1734s,
1538s, 1519m, 1435w, 1344s, 1225s, 1179w, 1096w,
1051m, 947w, 907w, 829m, 777w, 728s, 668w, 606w.
C(arom)); 131.34, 127.80, 127.73 (3d, C(arom)); 121.13
(s, C(arom)); 99.21, 99.11, 98.68, 98.64, 98.61, 98.45,
97.28, 97.12 (8d, C(THP)); 84.83, 84.58, 84.32, 84.16
(4d, C(400)); 80.00, 79.89, 79.80, 79.65, 79.37, 79.30,
78.29, 78.01 (8d, C(100), C(300)); 68.46, 68.23, 68.03,
63.16, 62.36, 62.23, 62.17, 62.05, 61.83, 61.64 (10t,
C(500), C(THP)); 42.58, 42.36, 41.47, 41.14 (4t, C(200));
31.08, 31.07, 30.87, 30.82, 30.73, 30.55, 30.45, 30.41,
25.43, 19.96, 19.43, 19.40, 19.35, 19.32, 19.12, 19.04
(16t, C(THP)). HR-ESI+-MS: m/z 463.1093 ([M+Na]+;
C21H29BrO5Na calcd 463.1096). IR (neat): tmax 2939m,
2868w, 1486w, 1439w, 1350w, 1259w, 1201w, 1122s,
1070s, 1009s, 968s, 904m, 870m, 814s.
4.2. General procedure for Suzuki coupling
Method A. A mixture of 3c (1 equiv), phenylboronic acid
(1.5 equiv), KF (3 equiv), Pd(OAc)2 (1 mol%), and 2-(di-
tert-butylphosphino)biphenyl (2 mol%) in dry THF
(1 ml/mmol) was stirred at room temperature over 16 h
in a sealed flask. The mixture was poured into water
and extracted with CH2Cl2. The combined organic phas-
es were washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo. Purification by FC (silica gel,
hexane/EtOAc) yielded the desired compounds.
4.2.2. 40-(300,500-Di-O-acetyl-200-deoxy-b-D-ribofuranosyl)-
4-nitrobiphenyl (4b). Method C. Yellow crystals (239 mg,
0.6 mmol, 82%) that can be recrystallized from CH2Cl2/
hexane. Rf 0.3 (hexane/EtOAc 7:3). 1H NMR (300 MHz,
CDCl3): d 8.30 (d, 2H, J = 8.9, H-C(arom)); 7.73 (d, 2H,
J = 8.9, 8.9, H-C(arom)); 7.62 (d, 2H, J = 8.5,
H-C(arom)); 7.48 (d, 2H, J = 8.3, H-C(arom)); 5.26 (d,
1H, J = 6.2, H-C(300)); 5.18 (dd, 1H, J1 = 5.1, J2 = 10.8,
H-C(100)); 4.42 (dd, 1H, J1 = 5.5, J2 = 12.8, H-C(500));
4.33–4.25 (m, 2H, H-C(400), H-C(500)); 2.41 (ddd, 1H,
J1 = 0.9, J2 = 5.1, J3 = 13.8, H-C(200)); 2.14, 2.10 (2s,
6H, 2· CH3); 2.13–2.03 (m, 1H, H-C(200)). 13C NMR
(101 MHz, CDCl3): d 170.70, 170.56 (2s, 2· (C@O));
147.17, 147.15, 141.67, 138.36 (4s, C(arom)); 127.73,
127.56, 126.59, 124.15 (4d, C(arom)); 82.79 (d, C(400));
80.18 (d, C(100)); 77.22 (d, C(300)); 64.36 (t, C(500));
41.28 (t, C(200)); 21.10, 20.88 (2q, 2· CH3). HR-EI-MS:
m/z 399.1321 (M+; C21H21NO7; calcd 399.1318). IR
(KBr): tmax 2913w, 2878w, 1749s, 1734s, 1602m,
1594m, 1514s, 1489w, 1430w, 1380m, 1341s, 1297w,
1266m, 1243s, 1217s, 1177m, 1111w, 1091m, 1073m,
1050m, 1021w, 952w, 927m, 872w, 859w, 825m, 760w,
752w, 736w, 697w, 675w, 661w, 630w, 585w, 559w,
506w.
Method B. Same procedure, but 3d as starting material.
Method C. A solution of 3b (1 equiv), pinacolboronate
(1.5 equiv), and K3PO4 (3 equiv) in dry DMF (5 ml/
mmol) was degassed by bubbling Ar through it for
15 min. Pd(PPh3)4 (3 mol%) was added and the solution
was heated to 85 ꢁC. After 16 h, the mixture was allowed
to cool to room temperature and was diluted with
CH2Cl2. The mixture was washed with 2 M NaOH solu-
tion. The combined aqueous phases were extracted with
CH2Cl2. The combined organic phases were washed
with brine, dried (MgSO4), filtered, and concentrated
in vacuo. The crude product and DMAP (0.2 equiv)
were dissolved in dry pyridine (6 ml/equiv) and the solu-
tion was cooled to 0 ꢁC. Ac2O (2.6 equiv) was added
dropwise. The mixture was stirred at room temperature
for 16 h and then diluted with CH2Cl2. The mixture was
washed with water and brine and the combined aqueous
phases were extracted with CH2Cl2 (3·). The combined
organic phases were dried (MgSO4), filtered and concen-
trated in vacuo. Purification by FC (silica gel, hexane/
EtOAc) yielded the desired compounds.
4.2.3. 40-(300,500-Di-O-acetyl-200-deoxy-b-D-ribofuranosyl)-
3-methoxybiphenyl (4c). Method A. Colorless oil
(130 mg, 0.34 mmol, 94%). Rf 0.4 (hexane/EtOAc 8:3).
1H NMR (300 MHz, CDCl3): d 7.58 (d, 2H, J = 8.3,
H-C(arom)); 7.45–7.32 (m, 3H, H-C(arom)); 7.20–7.09
(m, 2H, H-C(arom)); 6.90 (ddd, 1H, J1 = 0.8, J2 = 2.5,
J3 = 8.2, H-C(arom)); 5.25 (d, 1H, J = 6.2, H-C(300));
5.16 (dd, 1H, J1 = 5.1, J2 = 10.9, H-C(100)); 4.41 (dd,
1H, J1 = 5.8, J2 = 13.4, H-C(500)); 4.32–4.23 (m, 2H,
H-C(400), H-C(500)); 3.86 (s, 3H, –OCH3); 2.38 (ddd,
1H, J1 = 0.9, J2 = 5.1, J3 = 13.8, H-C(200)); 2.14, 2.10
(2s, 6H, 2· CH3); 2.18–2.03 (m, 1H, H-C(200)). 13C
NMR (75 MHz, CDCl3): d 170.75, 170.58 (2s, (C@O));
159.97, 142.33, 140.79, 139.80 (4s, C(arom)); 129.78,
127.33, 126.29, 119.62, 112.88, 112.74 (6d, C(arom));
82.70 (d, C(400)); 80.43 (d, C(100)); 76.71 (d, C(300));
64.45 (t, C(500)); 55.31 (q, –OCH3); 41.22 (t, C(200));
Method D. Same procedure as for Suzuki coupling, but
protection of the crude product with THP using the fol-
lowing conditions: The crude product and TosOH (0.2
equiv) were dissolved in dry THF (6 ml/mmol) and
3,4-dihydro-2H-pyran (3 equiv) was added dropwise at
0 ꢁC. The mixture was stirred at room temperature for
16 h and then diluted with t-BuOMe. The mixture was
washed with sat. NaHCO3 solution, water, and brine,
and the combined aqueous phases were extracted with
t-BuOMe. The combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. Purifica-
tion by FC (silica gel, hexane/EtOAc) yielded the desired
compounds.

6180
A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
21.12, 20.89 (2q, 2· CH3). HR-EI-MS: m/z 384.1572
(M+; C22H24O6 calcd 384.1573). IR (neat): tmax 1736s,
1600w, 1565w, 1481w, 1435w, 1364w, 1296w, 1220s,
1175m, 1095w, 1051m, 1029m, 1014m, 946w, 866w,
829m, 780m, 732w, 696w, 606w.
4.42 (dd, 1H, J1 = 5.7, J2 = 13.0, H-C(500)); 4.33–4.25
(m, 2H, H-C(400), H-C(500)); 2.40 (ddd, 1H, J1 = 1.0,
J2 = 5.2, J3 = 13.75, H-C(200)); 2.15–2.05 (m, 1H,
H-C(200)); 2.14, 2.11 (2s, 6H, 2· CH3). 13C NMR
(75 MHz, CDCl3): d 170.70, 170.56 (2s, 2· (C@O));
148.79, 142.45, 141.24, 138.28 (4s, C(arom)); 132.94,
129.76, 127.33, 126.63, 122.11, 121.88 (6d, C(arom));
82.80 (d, C(400)); 80.21 (d, C(100)); 76.63 (d, C(300));
64.38 (t, C(500)); 41.30 (t, C(200)); 21.10, 20.88 (2q,
2· CH3). HR-EI-MS: m/z 399.1321 (M+; C21H21NO7
calcd 399.1318). IR (neat): tmax 1736s, 1530m, 1517m,
1434w, 1348s, 1225s, 1178w, 1098w, 1052m, 946w,
908w, 876w, 832w, 805w, 767w, 727s, 682w, 648w, 605w.
4.2.4. 40-(300,500-Di-O-acetyl-200-deoxy-b-D-ribofuranosyl)-
4-methoxybiphenyl (4d). Method A. Colorless crystals
(183 mg, 0.48 mmol, 95%) that can be recrystallized
from CH2Cl2/hexane. Rf 0.3 (hexane/EtOAc 8:2). 1H
NMR (300 MHz, CDCl3): d 7.57–7.49 (m, 4H, H-
C(arom)); 7.40 (d, 2H, J = 8.1, H-C(arom)); 6.97 (d,
2H, J = 8.9, H-C(arom)); 5.25 (d, 1H, J = 6.2, H-
C(300)); 5.15 (dd, 1H, J1 = 5.1, J2 = 10.7, H-C(100));
4.45–4.36 (m, 1H, H-C(500)); 4.32–4.22 (m, 2H, H-
C(400), H-C(500)); 3.85 (s, 3H, –OCH3); 2.37 (ddd, 1H,
J1 = 0.9, J2 = 5.1, J3 = 13.8, H-C(200)); 2.13, 2.10 (2s,
6H, 2· CH3); 2.17–2.05 (m, 1H, H-C(200)). 13C NMR
(75 MHz, CDCl3): d 170.77, 170.60 (2s, 2· (C@O));
159.23, 140.56, 138.92, 133.33 (4s, C(arom)); 128.11,
126.84, 126.32, 114.25 (4d, C(arom)); 82.66 (d, C(400));
80.49 (d, C(100)); 76.74 (d, C(300)); 64.47 (t, C(500));
55.36 (q, –OCH3); 41.19 (t, C(200)); 21.13, 20.89 (2q,
2· CH3). HR-EI-MS: m/z 384.1574 (M+); C22H24O6
calcd 384.1573. IR (KBr): tmax 2957w, 2877w, 1745s,
1607w, 1500m, 1448w, 1381m, 1321w, 1312w, 1287m,
1266s, 1247s, 1201m, 1177m, 115w, 1097w, 1076m,
1059s, 1036m, 1022m, 1001w, 966w, 942w, 867w, 816s,
710w, 666w, 651w, 605w, 524w.
4.2.7.
40-[300,500-Di-O-(2-tetrahydro-2H-pyranyl)-200-de-
oxy-b-D-ribofuranosyl]-4-nitrobiphenyl (4g). Method D.
Yellow oil (274 mg, 0.57 mmol, 65%). Rf 0.3 (hexane/
1
EtOAc 8:2). H NMR (300 MHz, CDCl3): d 8.28 (d,
2H, J = 8.9, H-C(arom)); 7.23 (d, 2H, J = 8.9, H-
C(arom)); 7.62–7.49 (m, 4H, H-C(arom)); 5.27–5.13
(m, 1H, H-C(100)); 4.78–4.68 (m, 2H, H-THP); 4.52–
4.40 (m, 1H, H-C(300)); 4.37–4.21 (m, 1H, H-C(400));
4.04–3.82 (m, 3H, H-C(500), H-THP); 3.68–3.48 (m,
3H, H-C(500), H-THP); 2.52–2.27 (m, 1H, H-C(200));
2.11–1.48 (m, 13H, H-C(200), H-THP). 13C NMR
(75 MHz, CDCl3): d 147.42, 147.03, 143.31, 143.24,
143.19, 137.86 (6s, C(arom)); 127.68, 127.33, 126.89,
126.86, 126.82, 126.80, 124.09 (7d, C(arom)); 99.25,
99.14, 98.73, 98.66, 98.58, 98.53, 97.31, 97.13 (8d,
C(THP)); 84.89, 84.62, 84.38, 84.22 (4d, C(400)); 80.21,
80.11, 80.02, 79.86, 79.45, 79.40, 78.34, 78.06 (8d,
C(100), C(300)); 68.50, 68.28, 68.09, 63.25, 62.38, 62.24,
62.20, 62.07, 61.88, 61.70 (10t, C(500), C(THP)); 42.59,
42.36, 41.47, 41.13 (4t, C(200)); 31.13, 30.89, 30.84,
30.59, 30.48, 30.44, 25.44, 20.01, 19.43, 19.38, 19.32,
19.15, 19.08 (13t, C(THP)). HR-ESI+-MS: m/z
506.2156 ([M+Na]+; C27H33NO7Na calcd 506.2154).
IR (neat): tmax 2939w, 2868w, 1736w, 1595w, 1515m,
1486w, 1441w, 1340s, 1240w, 1200w, 1179w, 1119m,
1073s, 1032s, 1019s, 970m, 905m, 868m, 854m, 823m,
757m, 729w, 696w, 643w, 625w, 605w.
4.2.5. 40-(300,500-Di-O-acetyl-200-deoxy-b-D-ribofuranosyl)-
3,4-dimethoxybiphenyl (4e). Method A. Colorless solid
(309 mg, 0.74 mmol, 93%). Rf 0.2 (hexane/EtOAc 7:3).
1H NMR (300 MHz, CDCl3): d 7.55 (d, 2H, J = 8.3,
H-C(arom)); 7.41 (d, 2H, J = 8.3, H-C(arom)); 7.17–
7.08 (m, 2H, H-C(arom)); 6.94 (d, 1H, J = 8.3,
H-C(arom)); 5.26 (d, 1H, J = 6.2, H-C(300)); 5.16 (dd,
1H, J1 = 5.1, J2 = 10.9, H-C(100)); 4.41 (dd, 1H,
J1 = 5.8, J2 = 13.4, H-C(500)); 4.32–4.24 (m, 2H,
H-C(400), H-C(500)); 3.95, 3.92 (2s, 6H, 2· –OCH3); 2.37
(dd, 1H, J1 = 5.1, J2 = 13.8, H-C(200)); 2.17–2.04 (m,
1H, H-C(200)); 2.14, 2.10 (2s, 6H, 2· CH3). 13C NMR
(75 MHz, CDCl3): d 170.75, 170.58 (2s, 2· (C@O));
149.21, 148.73, 140.76, 139.18, 133.82 (5s, C(arom));
126.97, 126.30, 119.38, 111.54, 110.43 (5d, C(arom));
82.67 (d, C(400)); 80.45 (d, C(100)); 76.72 (d, C(300)); 64.
45 (t, C(500)); 56.01, 55.97 (2q, 2· –OCH3); 41.22 (t,
C(200)); 21.12, 20.89 (2q, 2· CH3). HR-EI-MS: m/z
414.1677 (M+; C23H26O7 calcd 414.1679). IR (KBr):
tmax 2954w, 2842w, 1748s, 1734s, 1603w, 1589w,
1527w, 1507m, 1465w, 1444w, 1384w, 1371w, 1327w,
1248s, 1218s, 1186w, 1173m, 1146m, 1095w, 1053m,
1024m, 1004w, 987w, 948w, 882w, 851w, 831w, 808m,
764w, 608w, 586w, 547w.
4.2.8.
40-[300,500-Di-O-(2-tetrahydro-2H-pyranyl)-200-de-
oxy-b-D-ribofuranosyl]-3-nitrobiphenyl (4h). Method B.
Slightly yellow oil (324 mg, 0.67 mmol, 80%). Rf 0.2
(hexane/EtOAc 8:2). 1H NMR (300 MHz, CDCl3): d
8.44 (t, 1H, J = 2.1, H-C(arom)); 8.22–8.15 (m, 1H,
H-C(arom)); 7.90 (d, 1H, J = 7.9, H-C(arom)); 7.64–
7.48 (m, 5H, H-C(arom)); 5.28–5.12 (m, 1H, H-C(100));
4.80–4.68 (m, 2H, H-THP); 4.53–4.40 (m, 1H,
H-C(300)); 4.37–4.20 (m, 1H, H-C(400)); 4.04–3.82 (m,
3H, H-C(500), H-THP); 3.69–3.48 (m, 3H, H-C(500),
H-THP); 2.52–2.27 (m, 1H, H-C(200)); 2.12–1.48 (m,
13H, H-C(200), H-THP). 13C NMR (75 MHz, CDCl3):
d 148.77, 142.86, 142.79, 142.73, 142.69, 137.80 (6s,
C(arom)); 132.95, 129.68, 127.09, 126.92, 126.90,
126.85, 126.83, 121.94, 121.85 (9d, C(arom)); 99.27,
99.17, 98.72, 98.64, 98.56, 98.51, 97.30, 97.12 (8d,
C(THP)); 84.89, 84.61, 84.37, 84.21 (4d, C(400)); 80.25,
80.14, 80.05, 79.89, 79.47, 79.40, 78.36, 78.07 (8d,
C(100), C(300)); 68.53, 68.30, 68.10, 63.23, 62.38, 62.24,
62.20, 62.08, 61.87, 61.68 (10t, C(500), C(THP)); 42.61,
42.38, 41.50, 41.15 (4t, C(200)); 31.13, 30.90, 30.84,
4.2.6. 40-(300,500-Di-O-acetyl-200-deoxy-b-D-ribofuranosyl)-
3-nitrobiphenyl (4f). Method A. Colorless oil (140 mg,
0.35 mmol, 97%). Rf 0.3 (hexane/EtOAc 7:3). 1H
NMR (300 MHz, CDCl3): d 8.45 (t, 1H, J = 2.1, H-
C(arom)); 8.24–8.17 (m, 1H, H-C(arom)); 7.93–7.89
(m, 1H, H-C(arom)); 7.65–7.58 (m, 2H, H-C(arom));
7.48 (d, 1H, J = 8.1, H-C(arom)); 5.26 (d, 1H, J = 6.4,
H-C(300)); 5.19 (dd, 1H, J1 = 5.1, J2 = 10.9, H-C(100));

A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
6181
30.60, 30.48, 30.45, 25.49, 25.45, 20.00, 19.44, 19.39,
19.32, 19.16, 19.07 (14t, C(THP)). HR-EI-MS: m/z
483.2253 (M+; C27H33NO7 calcd 483.2257). IR (neat):
tmax 2939m, 2868w, 1529m, 1439w, 1348s, 1261w,
1201w, 1122s, 1070s, 1016s, 970s, 903m, 874m, 808m,
766w, 727m, 681m.
2H, H-THP); 4.55 (d, 2H, J = 6.6, H-Fmoc); 4.51–4.38
(m, 1H, H-C(300)); 4.35–4.18 (m, 2H, H-C(400), H-Fmoc);
4.02–3.81 (m, 3H, H-C(500), H-THP); 3.66–3.47 (m, 3H,
H-C(500), H-THP); 2.49–2.23 (m, 1H, H-C(200)); 2.11–
1.47 (m, 13H, H-C(200), H-THP). 13C NMR (75 MHz,
CDCl3): d 153.40 (s, C@O); 143.72, 141.98, 141.35,
139.86, 138.11 (5s, C(arom)); 129.40, 127.76, 127.11,
127.05, 126.53, 126.51, 126.47, 126.45, 124.92, 122.37,
120.12, 117.57 (12d, C(arom)); 99.24, 99.14, 98.66,
98.57, 98.46, 98.40, 97.21, 97.04 (8d, C(THP)); 84.75,
84.47, 84.26, 84.08 (4d, C(400)); 80.39, 80.28, 80.18,
80.02, 79.45, 79.40, 78.34, 78.06 (8d, C(100), C(300));
68.52, 68.28, 68.10, 66.02, 63.13, 62.31, 62.16, 62.14,
62.02, 61.81, 61.60 (11t, C(500), C(THP), C(Fmoc));
47.14 (d, C(Fmoc)); 42.47, 42.22, 41.35, 40.99 (4t,
C(200)); 31.09, 30.86, 30.81, 30.55, 30.44, 30.40, 25.42,
19.95, 19.40, 19.34, 19.28, 19.10, 19.00 (13t, C(THP)).
HR-ESI+-MS: m/z 698.3069 ([M+Na]+; C42H45NO7Na
calcd 698.3093). IR (KBr): tmax 2942s, 2869m, 1735s,
1610m, 1596m, 1550m, 1516w, 1487w, 1452m, 1403w,
1353w, 1321w, 1210s, 1125m, 1075s, 1035s, 971m,
905w, 870w, 832w, 789w, 760m, 741s, 697w, 622w,
543w.
4.2.9. General procedure for the preparation of the
biphenylamines. To solutions of the nitro-biphenyl-nu-
cleosides 4g–h (1 equiv) in EtOAc (5 ml/mmol) and
MeOH (1 ml/mmol) was added Pd/C (10% w/w) and
the suspensions were stirred under 1 atm H2 at room
temperature for 4 h. The suspensions were filtered over
celite, washed with EtOAc, and concentrated in vacuo.
i
The crude products, Fmoc-Cl (2.2 equiv) and Pr2NEt
(2.2 equiv), were dissolved in CH2Cl2 (6 ml/mmol).
The solutions were stirred at room temperature for
16 h and then diluted with CH2Cl2. The mixtures were
washed with sat. NaHCO3 solution, water, and brine,
and the combined aqueous phases were extracted with
CH2Cl2. The combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. Purifica-
tion by FC (silica gel) yielded the desired Fmoc-protect-
ed amino-compounds 5a–b.
4.2.12. General procedure for O-deprotection. Method A.
Suspensions of the acetylated nucleosides 4 (1 equiv)
and K2CO3 (1 equiv) in dry MeOH (5 ml/mmol) were
stirred at room temperature over 36 h. The reaction mix-
tures were neutralized with 10% HCl solution and con-
centrated in vacuo. The residues were taken up in
CH2Cl2 and washed with water and brine. The com-
bined aqueous phases were extracted with CH2Cl2.
The combined organic phases were dried (MgSO4), fil-
tered, and concentrated in vacuo. Purification by FC
(silica gel) yielded the desired nucleosides 6.
4.2.10. 40-(300,500-Di-O-(2-tetrahydro-2H-pyranyl)-200-de-
oxy-b-D-ribofuranosyl)-4-Fmoc-aminobiphenyl (5a). Col-
orless foam (489 mg, 0.72 mmol, 67%). Rf 0.2 (hexane/
1
EtOAc 8:2). H NMR (300 MHz, CDCl3): d 7.78 (d,
2H, J = 7.4, H-C(arom)); 7.63 (d, 2H, J = 7.4, H-
C(arom)); 7.55–7.29 (m, 12H, H-C(arom)); 6.83 (s, 1H,
–NH–); 5.23–5.10 (m, 1H, H-C(100)); 4.77–4.67 (m, 2H,
H-THP); 4.56 (d, 2H, J = 6.6, H-Fmoc); 4.52–4.38 (m,
1H, H-C(300)); 4.34–4.18 (m, 2H, H-C(400), H-Fmoc);
4.02–3.80 (m, 3H, H-C(500), H-THP); 3.66–3.48 (m,
3H, H-C(500), H-THP); 2.49–2.24 (m, 1H, H-C(200));
2.12–1.47 (m, 13H, H-C(200), H-THP). 13C NMR
(75 MHz, CDCl3): d 153.39 (s, C@O); 143.75, 141.39,
140.99, 140.91, 140.88, 139.71, 136.95, 136.31 (8s,
C(arom)); 127.80, 127.62, 127.14, 126.69, 126.58,
126.54, 124.94, 120.06, 119.14 (9d, C(arom)); 99.26,
99.15, 98.68, 98.59, 98.48, 98.44, 97.22, 97.05 (8d,
C(THP)); 84.75, 84.47, 84.27, 84.09 (4d, C(400)); 80.43,
80.33, 80.22, 80.07, 79.48, 79.44, 78.35, 78.09 (8d,
C(100), C(300)); 68.55, 68.34, 68.31, 68.14, 63.88, 63.18,
62.32, 62.16, 62.03, 61.83, 61.62 (11t, C(500), C(THP),
C(Fmoc)); 47.18 (d, C(Fmoc)); 42.46, 42.22, 41.35,
40.98 (4t, C(200)); 31.11, 30.89, 30.85, 30.57, 30.47,
30.43, 25.45, 19.99, 19.42, 19.36, 19.30, 19.12, 19.03
(13t, C(THP)). HR-ESI+-MS: m/z 698.3109 ([M+Na]+;
C42H45NO7Na calcd 698.3093). IR (KBr): tmax 2943s,
2868m, 1735s, 1596m, 1571w, 1535s, 1479w, 1452m,
1422w, 1402w, 1353w, 1319m, 1216s, 1125m, 1075s,
1034s, 971m, 905w, 869w, 818m, 759m, 741m, 622w,
526w.
Method B. To solutions of the THP-protected nucleo-
sides 5 (1 equiv) in MeOH (5 ml/mmol) and CH2Cl2
(2 ml/mmol) was added TsOH (10 mol%) and the sus-
pensions were stirred at room temperature for 4 h. The
reaction mixtures were diluted with CH2Cl2 and washed
with sat. NaHCO3 solution, water, and brine. The com-
bined aqueous phases were extracted with CH2Cl2. The
combined organic phases were dried (MgSO4), filtered,
and concentrated in vacuo. Purification by FC (silica
gel) yielded the desired nucleosides 6.
4.2.13. 40-(200-Deoxy-b-D-ribofuranosyl)-3,5-dinitrobiphe-
nyl (6a). Method A. Yellow solid (226 mg, 0.68 mmol,
92%). Rf 0.3 (EtOAc). 1H NMR (300 MHz, MeOD-
d4): d 8.93 (t, 1H, J = 2.1, H-C(4)); 8.82 (d, 2H,
J = 2.1, H-C(2); H-C(6)); 7.78 (d, 2H, J = 8.5, H(arom))
7.60 (d, 2H, J = 8.1, H(arom)); 5.20 (dd, 1H, J1 = 5.3,
J2 = 10.4, H-C(100)); 4.38–4.33 (m, 1H, H-C(300)); 3.98
(dt, 1H, J1 = 2.3, J2 = 5.1, H-C(400)); 3.75–3.64 (m, 2H,
2· H-C(500)); 2.27 (ddd, 1H, J1 = 1.5, J2 = 5.5,
J3 = 13.1, H-C(200)); 2.01–1.91 (m, 1H, H-C(200)). 13C
NMR (101 MHz, MeOD-d4): d 150.51, 145.58, 145.35,
137.19 (4s, C(arom)); 128.38, 128.26, 127.71, 117.95
(4d, C(arom)); 89.43 (d, C(400)); 81.07 (d, C(100));
74.47(d, C(300)); 64.09 (t, C(500)); 45.09 (t, C(200)). HR-
EI-MS: m/z 360.0958 (M+; C17H16N2O7 calcd
360.0958). IR (neat): tmax 3310br, 3076w, 2944w,
4.2.11. 40-(300,500-Di-O-(2-tetrahydro-2H-pyranyl)-200-de-
oxy-b-D-ribofuranosyl)-3-Fmoc-aminobiphenyl (5b). Col-
orless foam (383 mg, 0.57 mmol, 64%). Rf 0.2 (hexane/
1
EtOAc 8:2). H NMR (300 MHz, CDCl3): d 7.77 (d,
2H, J = 7.5, H-C(arom)); 7.65–7.50 (m,
5
H,
H-C(arom)); 7.47–7.26 (m, 9H, H-C(arom)); 6.83 (s,
1H, –HN–); 5.23–5.09 (m, 1H, H-C(100)); 4.77–4.67 (m,

6182
A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
2359w, 1612w, 1536s, 1513m, 1340s, 1315m, 1170w,
1081w, 1056m, 1042m, 1013m, 971w, 938w, 918m,
848w, 831m, 778w, 741m, 725s, 666m, 609m.
(d, C(100)); 74.53 (d, C(300)); 64.15 (t, C(500)); 55.79 (q,
–OCH3); 44.95 (t, C(200)). HR-EI-MS: m/z 300.1364
(M+; C18H20O4 300.1362). IR (KBr): tmax 3402br,
2932w, 1607m, 1583w, 1530w, 1501s, 1459w, 1445w,
1401w, 1313w, 1289w, 1270w, 1253s, 1188m, 1090m,
1034s, 1000m, 868w, 813s, 608w, 579w, 517w.
4.2.14. 40-(200-Deoxy-b-D-ribofuranosyl)-4-nitrobiphenyl
(6b). Method A. Yellow solid (241 mg, 0.76 mmol,
96%). Rf 0.3(EtOAc). H NMR (300 MHz, MeOD-d4):
1
d 8.28 (d, 2H, J = 8.9, H-C(arom)); 7.34 (d, 2H,
J = 8.9, H-C(arom)); 7.68 (d, 2H, J = 8.3, H-C(arom));
7.53 (d, 2H, J = 8.1, H-C(arom)); 5.19 (dd, 1H,
J1 = 5.3, J2 = 10.5, H-C(100)); 4.38–4.32 (m, 1H,
H-C(300)); 3.70 (dt, 1H, J1 = 2.5, J2 = 5.1, H-C(400));
3.75–3.64 (m, 2H, 2· H-C(500)); 2.25 (ddd, 1H, J1 = 1.7,
J2 = 5.5, J3 = 13.1, H-C(200)); 2.02–1.91 (m, 1H,
H-C(200)). 13C NMR (75 MHz, MeOD-d4): d 148.58,
148.48, 144.46, 139.19 (4s, C(arom)); 128.82, 128.39,
127.97, 125.08 (4d, C(arom)); 89.37 (d, C(400)); 81.17
(d, C(100)); 74.48 (d, C(300)); 64.11 (t, C(500)); 45.03 (t,
C(200)). HR-EI-MS: m/z 315.1107 (M+; C17H17NO5
calcd 315.1107). IR (KBr): tmax 3257br, 2931m,
2369w, 1596s, 1570w, 1512s, 1488s, 1474m, 1426m,
1398w, 1346s, 1282m, 1219w, 1175m, 1112m, 1090s,
1073m, 1047s, 1002s, 947m, 929w, 899w, 856s, 830s,
756s, 727m, 694m, 612w, 558w, 512w, 458w.
4.2.17. 40-(200-Deoxy-b-D-ribofuranosyl)-3,4-dimethoxybi-
phenyl (6e). Method A. Colorless solid (226 mg,
0.68 mmol, 92%). Rf 0.3 (EtOAc). 1H NMR
(300 MHz, MeOD-d4): d 7.55 (d, 2H, J = 8.3, H-
C(arom)); 7.43 (d, 2H, J = 8.3, H-C(arom)); 7.20–7.13
(m, 2H, H-C(arom)); 7.00 (d, 1H, J = 8.5, H-C(arom));
5.15 (dd, 1H, J1 = 5.5, J2 = 10.5, H-C(100)); 4.37–4.31
(m, 1H, H-C(300)); 3.96 (dt, 1H, J1 = 2.5, J2 = 5.1,
H-C(400)); 3.89, 3.85 (2s, 6H, 2· –OCH3); 3.74–3.63 (m,
2H, 2· H-C(500)); 2.21 (ddd, 1H, J1 = 1.7, J2 = 5.5,
J3 = 13.1, H-C(200)); 2.03–1.92 (m, 1H, H-C(200)). 13C
NMR (75 MHz, MeOD-d4): d 150.79, 150.24, 141.81,
141.63, 135.43 (5s, C(arom)); 127.66, 127.64, 120.57,
113.40, 112.01 (5d, C(arom)); 89.26 (d, C(400)); 81.44
(d, C(100)); 74.51 (d, C(300)); 64.14 (t, C(500)); 56.63,
56.58 (2s, 2· –OCH3); 44.96 (t, C(200)). HR-EI-MS: m/z
330.1468 (M+; C19H22O5 calcd 330.1467). IR (KBr):
tmax 2934m, 2884w, 2838w, 1601w, 1590m, 1564w,
1528m, 1507s, 1460m, 1439w, 1401m, 1327m, 1276m,
1250s, 1218s, 1171s, 1140s, 1102m, 1088m, 1053s,
1023s, 997w, 937w, 909w, 880w, 832m, 808s, 767m,
738w, 654w, 618w, 587w, 541w.
4.2.15. 40-(200-Deoxy-b-D-ribofuranosyl)-3-methoxybiphe-
nyl (6c). Method A. Colorless solid (297 mg, 0.99 mmol,
94%). Rf 0.3 (EtOAc). H NMR (300 MHz, MeOD-d4):
1
d 7.57 (d, 2H, J = 8.5, H-C(arom)); 7.46 (d, 2H, J = 8.1,
H-C(arom)); 7.33 (t, 1H, J = 8.1, H-C(arom)); 7.20–7.11
(m, 2H, H-C(arom)); 6.89 (ddd, 1H, J1 = 0.9, J2 = 2.5,
J3 = 8.2, H-C(arom)); 5.16 (dd, 1H, J1 = 5.3, J2 = 10.5,
H-C(100)); 4.37–4.31 (m, 1H, H-C(300)); 3.96 (dt, 1H,
J1 = 2.5, J2 = 5.2, H-C(400)); 3.84 (s, 3H, –OCH3);
3.74–3.64 (m, 2H, H-C(500)); 2.22 (ddd, 1H, J1 = 1.7,
J2 = 5.5, J3 = 13.1, H-C(200)); 2.04–1.92 (m, 1H,
H-C(200)). 13C NMR (75 MHz, DMSO-d6): d 159.90,
142.31, 141.76, 139.19 (4s, 4· C(arom)); 130.15,
126.77, 126.71, 119.13, 113.05, 112.35 (6d, 8· C(arom));
88.01 (d, C(400)); 79.12 (d, C(100)); 72.67 (d, C(300)); 62.69
(t, C(500)); 55.28 (q, –OCH3), 43.79 (t, C(200)). HR-EI-
MS: m/z 300.1361 (M+; C18H20O4 calcd 300.1362). IR
(KBr): tmax 3403br, 3003w, 2886m, 2838w, 1608s,
1787m, 1569m, 1522w, 1484s, 1439w, 1408m, 1344w,
1316m, 1299s, 1215s, 1173m, 1097m, 1064s, 1053s,
1028s, 1015m, 997s, 965w, 948w, 930w, 849w, 832m,
788s, 777s, 718w, 700w, 688w, 620w, 587w, 568w,
548w, 468w.
4.2.18. 40-(200-Deoxy-b-D-ribofuranosyl)-3-nitrobiphenyl
(6f). Method A. Slightly yellow solid (329 mg,
1.04 mmol, 88%) that can be recrystallized from
CH2Cl2/hexane. Rf 0.3 (EtOAc). 1H NMR
(300 MHz, MeOD-d4): d 8.46 (t, 1H, J = 1.9, H-
C(arom)); 8.21 (ddd, 1H, J1 = 0.9, J2 = 2.3, J3 = 8.3,
H-C(arom)); 8.04 (ddd, 1H, J1 = 0.9, J2 = 1.8,
J3 = 7.8, H-C(arom)); 7.73–7.65 (m, 3H, H-C(arom));
7.55 (d, 2H, J = 8.1, H-C(arom)); 5.19 (dd, 1H,
J1 = 5.5, J2 = 10.6, H-C(100)); 4.38–4.32 (m, 1H,
H-C(300)); 3.98 (dt, 1H, J1 = 2.5, J2 = 5.1, H-C(400));
3.75–3.64 (m, 2H, H-C(500)); 2.25 (ddd, 1H, J1 = 1.7,
J2 = 5.5; J3 = 13.0, H-C(200)); 2.04–1.92 (m, 1H,
H-C(200)). 13C NMR (75 MHz, DMSO-d6): d 148.64,
143.50, 141.83, 136.90 (4s, 4· C(biph)); 133.42,
130.69, 127.04, 127.00, 122.24, 121.16 (6d, 8· C(biph));
88.09 (d, C(400)); 79.02 (d, C(100)); 72.65 (d, C(300));
62.66 (t, C(500)); 43.82 (t, C(200)). HR-EI-MS: m/z
315.1107 (M+; C17H17NO5 calcd 315.1107). IR
(KBr): tmax 3372br; 3089w, 3034w, 2940w, 2913m,
2887m, 1615w, 1585w, 1535s, 1517s, 1476w, 1440w,
1411w, 1361s, 1349s, 1317m, 1270m, 1231w, 1174w,
1069s, 1037m, 994m, 974m, 928w, 898w, 877w,
863w, 840m, 830m, 807m, 767m, 743m, 728m, 685m,
649w, 585w, 540w, 496w, 466w.
4.2.16. 40-(200-Deoxy-b-D-ribofuranosyl)-4-methoxybiphe-
nyl (6d). Method A. Colorless solid (220 mg,
0.73 mmol, 94%) that can be recrystallized from
CHCl3/hexane: Rf 0.3 (EtOAc); 1H NMR (300 MHz,
MeOD-d4): d 7.53 (d, 4H, J = 7.9, H-C(arom)); 7.43
(d, 2H, J = 8.1, H-C(arom)); 6.97 (d, 2H, J = 8.9,
H-C(arom)); 5.15 (dd, 1H, J1 = 5.5, J2 = 10.6,
H-C(100)); 4.37–4.31 (m, 1H, H-C(300)); 3.96 (dt, 1H,
J1 = 2.5, J2 = 5.1, H-C(400)); 3.82 (s, 3H, –OCH3);
3.74–3.63 (m, 2H, H-C(500)); 2.21 (ddd, 1H, J1 = 1.7,
J2 = 5.5, J3 = 13.1, H-C(200)); 2.04–1.92 (m, 1H,
H-C(200)). 13C NMR (75 MHz, MeOD-d4): d 160.79,
141.58, 141.53, 134.66 (4s, C(arom)); 128.96, 127.69,
127.49, 115.30 (4d, C(arom)); 89.25 (d, C(400)); 81.47
4.2.19. 40-(200-Deoxy-b-D-ribofuranosyl)-4-Fmoc-aminobi-
phenyl (6g). Method B, but without extraction. Com-
pound 6g is highly insoluble in any common solvent
except pyridine. Therefore, the reaction mixture was just
concentrated in vacuo and coevaporated with pyridine.
The crude product was used for the tritylation step with-
out further purification and characterization.

A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
6183
4.2.20. 40-(200-Deoxy-b-D-ribofuranosyl)-3-Fmoc-aminobi-
phenyl (6h). Method B. Colorless solid (249 mg,
49 mmol, 89%). Rf 0.3 (EtOAc/hexane 8:2). H NMR
4.2.23. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-b-D-ribofuranosyl]-4-nitrobiphenyl (7b). Yellow foam
(436 mg, 0.71 mmol, 92%). Rf 0.4 (hexane/EtOAc
1
1
(300 MHz, acetone-d6): d 8.97 (br, 1H, H-N); 7.88 (d,
3H, J = 7.4, H-C(arom)); 7.78–7.72 (m, 2H, H-
C(arom)); 7.63–7.28 (m, 11H, H-C(arom)); 5.16 (dd,
1H, J1 = 5.5, J2 = 10.5, H-C(100)); 4.52 (d, 2H, J = 6.8,
H-C(Fmoc)); 4.44–4.38 (m, 1H, H-C(300)); 4.32 (t, 1H,
J = 6.8, H-C(Fmoc)); 4.23 (d, 1H, J = 3.8, –OH); 3.97
(dt, 1H, J1 = 2.5, J2 = 5.0, H-C(400)); 3.85 (t, 1H,
J = 5.8, –OH); 3.75–3.60 (m, 2H, H-C(500)); 2.24 (ddd,
1H, J1 = 1.7, J2 = 5.4, J3 = 12.8, H-C(200)); 1.99–1.88
(m, 1H, H-C(200)). 13C NMR (75 MHz, acetone-d6): d
154.46 (s, C@O); 145.01, 143.23, 142.43, 142.19,
140.69, 140.66 (6s, C(arom)); 130.17, 128.59, 127.98,
127.50, 127.43, 126.03, 122.10, 120.87, 118.16, 117.76
(10d, C(arom)); 89.18 (d, C(400)); 80.40 (d, C(100));
74.18 (d, C(300)); 67.07, 64.06 (2t, C(500), C(Fmoc));
48.01 (d, C(Fmoc)); 45.14 (t, C(200)). HR-ESI+-MS:
m/z 508.2143 ([M+Na]+; C32H29NO5Na calcd
508.2123). IR (KBr): tmax 3423br, 3320s, 3065w,
2917w, 2878w, 1697s, 1611m, 1547s, 1519w, 1490m,
1462w, 1451m, 1434m, 1399w, 1313m, 1290m, 1274m,
1249s, 1230s, 1103m, 1093m, 1062m, 1040m, 945w,
899w, 878w, 831w, 793m, 761m, 740s, 713w, 694w,
647w, 622w, 586w, 548w.
1:1 + 1% Et3N). H NMR (300 MHz, CDCl3): d 8.28
(d, 2H, J = 8.9, H(arom)); 7.72 (d, 2H, J = 8.9,
H(arom)); 7.60 (d, 2H, J = 8.3, H(arom)); 7.53–7.45
(m, 6H, H(arom)); 7.40–7.17 (m, 7H, H(arom)); 6.83
(d, 4H, J = 8.9, H(arom)); 5.24 (dd, J1 = 5.7, J2 = 10.2,
1H, H-C(100)); 4.49–4.43 (m, 1H, H-C(300)); 4.14–4.07
(m, 1H, H-C(400)); 3.78 (s, 6H, 2· CH3O-DMT); 3.41–
3.28 (m, 2H, H-C(500)); 2.30 (ddd, J1 = 2.1, J2 = 5.6,
J3 = 13.1, 1H, H-C(200)); 2.13–2.02 (m, 1H, H-C(200)).
13C NMR (75 MHz, CDCl3): d 158.53, 147.33, 147.07,
144.85, 142.99, 137.91, 136.03, 136.02 (8s, C(arom));
130.12, 128.21, 127.85, 127.68, 127.37, 126.84, 126.78,
124.12, 113.16 (9d, C(arom)); 86.50 (d, C(400)); 86.30
(s, C(Ph)3DMT); 79.55 (d, C(100)); 74.64 (d, C(30));
64.44 (t, C(500)); 55.22 (q, CH3O-DMT); 43.91 (t,
C(200)). HR-ESI+-MS: m/z 640. 2277 ([M+Na]+;
C38H35NO7Na calcd 640.2311). IR (KBr): tmax 2932w,
2837w, 1735w, 1605m, 1510s, 1464w, 1446w, 1397w,
1343s, 1302m, 1251s, 1177s, 1111m, 1082m, 1034s,
856w, 827s, 791w, 757m, 727w, 700w, 584w.
4.2.24. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-b-D-ribofuranosyl]-3-methoxybiphenyl (7c). Colorless
foam (420 mg, 0.70 mmol, 90%). Rf 0.3 (hexane/EtOAc
1
4.2.21. General procedure for DMT-protection. The
nucleosides 6 (1 equiv) were coevaporated with pyridine
(3·) and dissolved in pyridine (4 ml/mmol). DMT-Cl
was added in portions over 2 h (4 · 0.3 equiv). After
another 90 min at room temperature, the mixtures were
diluted with EtOAc and washed with sat. NaHCO3 solu-
tion. The combined aqueous phases were extracted with
EtOAc. The combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. The resi-
dues were coevaporated with toluene. Purification by
FC (silica gel) yielded the desired tritylated compounds 7.
1:1 + 1% Et3N). H NMR (300 MHz, CDCl3): d 7.54
(d, 2H, J = 8.5, H(arom)); 7.51–7.41 (m, 4H, H(arom));
7.40–7.13 (m, 9H, H(arom)); 7.11 (t, 1H, J = 2.5,
H(arom)); 6.89 (ddd, 1H, J1 = 1.0, J2 = 2.6, J3 = 10.4,
H(arom)); 6.82 (d, 4H, J = 9.0, H(arom)); 5.22 (dd,
1H, J1 = 5.7, J2 = 10.0, H-C(100)); 4.49–4.41 (m, 1H, H-
C(300)); 4.12–4.04 (m, 1H, H-C(400)); 3.86 (s, 3H,
–OCH3); 3.78 (s, 6H, 2· (DMT)-OCH3); 3.38 (dd, 1H,
J1 = 4.5, J2 = 9.6, H-C(500)); 3.29 (dd, 1H, J1 = 5.5,
J2 = 9.5, H-C(500)); 2.28 (ddd, 1H, J1 = 2.1, J2 = 5.8,
J3 = 13.1, H-C(200)); 2.14–2.03 (m, 1H, H-C(200)). 13C
NMR (75 MHz, CDCl3): d 159.95, 158.51, 144.87,
142.48, 141.08, 140.35, 136.06 (7s, C(arom)); 130.11,
129.74, 128.22, 127.85, 127.15, 126.81, 126.44, 119.62,
113.16, 112.84, 112.66 (11d, C(arom)); 86.35 (d, C(400));
86.26 (s, C(Ph)3DMT); 79.76 (d, C(100)); 74.75 (d,
C(300)); 64.52 (t, C(500)); 55.31, 55.21 (2q, 2· –OCH3);
43.83 (t, C(200)). HR-ESI+-MS: m/z 625.2589
([M+Na]+; C39H38O6Na calcd 625.2566). IR (neat): tmax
2932w, 2835w, 1606m, 1507m, 1482w, 1445w, 1404w,
1297m, 1248s, 1219m, 1174s, 1080m, 1031s, 951w,
826s, 778m, 745w, 727w, 699m, 634w, 602w.
4.2.22. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-b-D-ribofuranosyl]-3,5-dinitrobiphenyl (7a). Orange
foam (580 mg, 0.88 mmol, 95%). Rf 0.3 (hexane/EtOAc
1
1:1 + 1% Et3N). H NMR (300 MHz, CDCl3): d 9.00
(t, 1H, J = 2.1, H-C(arom)); 8.75 (d, 2H, J = 2.1, H-
C(arom)); 7.64 (d, 2H, J = 8.5, H-C(arom)); 7.60 (d,
2H, J = 8.3, H-C(arom)); 7.51–7.44 (m, 2H, H-
C(arom)); 7.40–7.18 (m, 7H, H-C(arom)); 6.83 (d, 4H,
J = 8.9, H-C(arom)); 5.26 (dd, 1H, J1 = 5.7, J2 = 10.2,
H-C(100)); 4.51–4.45 (m, 1H, H-C(300)); 4.15–4.08 (m,
1H, H-C(400)); 3.79 (s, 6H, CH3O-DMT); 3.43–3.28 (m,
2H, 2· H-C(500)); 3.35 (ddd, 1H, J1 = 2.1, J2 = 5.7,
J3 = 13.0); 2.13–2.02 (m, 1H, H-C(200)). 13C NMR
(75 MHz, CDCl3): d 158.55, 148.99, 144.82, 144.58,
144.22, 135.97, 135.48 (7s, C(arom)); 130.12, 128.21,
127.88, 127.21, 127.18, 126.87, 126.80, 117.04, 113.17
(9d, C(arom)); 86.59 (d, C(400)); 86.32 (s, C(Ph)3DMT);
79.39 (d, C(100)); 74.55 (d, C(300)); 64.38 (t, C(500));
55.24 (q, CH3O-DMT); 43.99 (t, C(200)). HR-ESI+-MS:
m/z 685.2144 ([M+Na]+; C38H34N2O9Na calcd
685.2162). IR (neat): tmax 2932w, 1607w, 1539s, 1507s,
1444w, 1344s, 1299w, 1247s, 1174s, 1078m, 1032s,
953w, 906w, 826s, 791w, 777w, 755w, 727s, 701m,
669w, 635w.
4.2.25. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-b-D-ribofuranosyl]-4-methoxybiphenyl (7d). Colorless
foam (420 mg, 0.70 mmol, 90%). Rf 0.4 (hexane/EtOAc
1
1:1 + 1% Et3N). H NMR (300 MHz, CDCl3): d 7.54–
7.17 (m, 15H, H(arom)); 6.97 (d, 2H, J = 8.9, H(arom));
6.82 (d, 4H, J = 8.9, H(arom)); 5.21 (dd, J1 = 5.7,
J2 = 10.0, 1H, H-C(100)); 4.48–4.41 (m, 1H, H-C(300));
4.11–4.05 (m, 1H, H-C(400)); 3.85 (s, 3H, CH3O–); 3.78
(s, 6H, 2· CH3O-DMT); 3.41–3.25 (m, 2H, H-C(500));
2.27 (ddd, J1 = 2.1, J2 = 5.7, J3 = 13.1, 1H, H-C(200));
2.14–2.03 (m, 1H, H-C(200)). 13C NMR (75 MHz,
CDCl3): d 159.15, 158.50, 144.88, 140.22, 140.10,
136.08, 133.50 (7s, C(arom)); 130.12, 128.24, 128.08,

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A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
127.85, 126.80, 126.66, 126.48, 114.22, 113.16 (9d,
C(arom)); 86.34 (d, C(400)); 86.27 (s, C(Ph)3DMT);
79.82 (d, C(100)); 74.74(d, C(30)); 64.55 (t, C(500)); 55.35,
55.22 (2q, 3· CH3O-); 43.80 (t, C(200)). HR-ESI+-MS:
m/z 625.2579 ([M+Na]+; C39H38O6Na calcd 625.2566).
IR (KBr): tmax 2932w, 2836w, 1736w, 1609m, 1583w,
1509s, 1464m, 1444m, 1295m, 1250s, 1177s, 1081m,
1037s, 1001m, 953w, 822m, 755w, 727w, 703w, 583w,
527w.
4.2.28. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-b-D-ribofuranosyl]-4-Fmoc-aminobiphenyl (7g). Col-
orless foam (469 mg, 0.51 mmol, 82%). Rf 0.4 (hexane/
1
EtOAc 1:1 + 1% Et3N). H NMR (300 MHz, CDCl3):
d 7.77 (d, 2H, J = 7.5, H(arom)); 7.61 (d, 2H, J = 7.4,
H(arom)); 7.54–7.16 (m 21H, H(arom)); 6.85–6.74 (m,
5H, H(arom), –NH–); 5.20 (dd, J1 = 5.5, J2 = 10.0, 1H,
H-C(100)); 4.56 (d, 2H, J = 6.6, H-Fmoc); 4.46–4.40 (m,
1H, H-C(300)); 4.27 (t, 1H, J = 6.4, H-Fmoc); 4.11–4.04
(m, 1H, H-C(400)); 3.76 (s, 6H, 2· CH3O-DMT); 3.40–
3.25 (m, 2H, H-C(500)); 2.26 (ddd, J1 = 2.1, J2 = 5.7,
J3 = 13.1, 1H, H-C(200)); 2.13–2.01 (m, 1H, H-C(200)).
13C NMR (75 MHz, CDCl3): d 158.50, 153.41, 144.88,
143.74, 141.38, 140.66, 139.73, 136.98, 136.19, 136.07
(10s, C(arom)); 130.11, 128.23, 127.84, 127.81, 127.59,
126.80, 127.15 126.71, 126.52, 124.93, 120.06, 119.16,
113.16 (13d, C(arom)); 86.35 (d, C(400)); 86.26 (s,
C(Ph)3DMT); 79.77 (d, C(100)); 74.72 (d, C(30)); 64.84,
64.54 (2t, C(500), C(Fmoc)); 55.21 (q, CH3O-DMT);
47.17 (d, C(Fmoc)); 43.81 (t, C(200)). HR-ESI+-MS: m/
z 832.3239 ([M+Na]+; C53H47NO7Na calcd 832.3250).
IR (KBr): tmax 2933w, 2836w, 1734s, 1608s, 1534s,
1509s, 1448m, 1420w, 1374w, 1318m, 1301m, 1251s,
1216s, 1177s, 1077s, 1034s, 824m, 791w, 824m, 758m,
741m, 702w, 621w, 585w, 545w.
4.2.26. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-b-D-ribofuranosyl]-3,4-dimethoxybiphenyl (7e). Color-
less foam (525 mg, 0.83 mmol, 90%). Rf 0.3 (hexane/
1
EtOAc 1:1 + 1% Et3N). H NMR (300 MHz, CDCl3):
d 7.54–7.40 (m, 6H, H-C(arom)); 7.37 (dd, 2H,
J1 = 1.5, J2 = 9.0, H-C(arom)); 7.33–7.17 (m, 3H, H-
C(arom)); 7.12 (dt, 2H, J1 = 2.1, J2 = 8.1, H-C(arom));
6.94 (d, 1H, J = 8.5, H-C(arom)); 6.83 (d, 4H, J = 8.9,
H-C(arom)); 5.21 (dd, 1H, J1 = 5.7, J2 = 10.0, H-
C(100)); 4.49–4.42 (m, 1H, H-C(400)); 4.12–4.05 (m, 1H,
C(300)); 3.94, 3.92 (2s, 6H, –OCH3); 3.78 (s, 6H,
(DMT)-OCH3); 2.32–2.23 (m, 2H, 2· H-C(500)); 2.28
(ddd, 1H, J1 = 2.1, J2 = 5.7; J3 = 13.1, H-C(200)); 2.15–
2.03 (m, 1H, H-C(200)). 13C NMR (75 MHz, CDCl3): d
158.50, 149.17, 148.63, 144.45, 140.45, 140.33, 136.08,
133.99 (8s, C(arom)); 130.12, 128.22, 127.85, 126.80,
126.46, 119.35, 113.15, 111.52, 110.45 (9d, C(arom));
86.35 (d, C(400)); 86.24 (s, C(Ph)3DMT); 79.78 (d,
C(100)); 74.74 (d, C(300)); 64.51 (t, C(500)); 56.00, 55.96,
55.21 (3s, 3· –OCH3); 43.86 (t, C(200)). HR-ESI+-MS:
m/z 655.2680 ([M+Na]+; C40H40O7Na calcd 655.2671).
IR (neat): tmax 2932w, 2835w, 1733w, 1606w, 1503s,
1444w, 1400w, 1300w, 1246s, 1217m, 1173s, 1143m,
1080m, 1027s, 953w, 882w, 827s, 806s, 764m, 727w,
702m.
4.2.29. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-b-D-ribofuranosyl]-3-Fmoc-aminobiphenyl (7h). Col-
orless foam (376 mg, 0.46 mmol, 96%). Rf 0.4 (hexane/
1
EtOAc 1:1 + 1% Et3N). H NMR (300 MHz, CDCl3):
d 7.77 (d, 2H, J = 7.5, H(arom)); 7.65–7.16 (m 23H,
H(arom)); 6.85–6.77 (m, 5H, H(arom), –NH–); 5.20
(dd, J1 = 5.7, J2 = 10.0, 1H, H-C(100)); 4.55 (d, 2H,
J = 6.6, H-Fmoc); 4.46–4.40 (m, 1H, H-C(300)); 4.27 (t,
1H, J = 6.6, H-Fmoc); 4.11–4.04 (m, 1H, H-C(400));
3.76 (s, 6H, 2· CH3O-DMT); 3.40–3.25 (m, 2H,
H-C(500)); 2.26 (ddd, J1 = 1.9, J2 = 5.7, J3 = 13.2, 1H,
H-C(200)); 2.12–2.01 (m, 1H, H-C(200)). 13C NMR
(75 MHz, CDCl3): d 158.47, 153.39, 144.83, 143.72,
141.88, 141.35, 141.17, 139.87, 138.12, 136.05 (10s,
C(arom)); 130.10, 130.08, 129.44, 128.20, 127.82,
127.77, 127.09, 126.79, 126.43, 124.91, 122.35, 120.03,
117.53, 113.14 (15d, C(arom)); 86.32 (d, C(400)); 86.25
(s, C(Ph)3DMT); 79.70 (d, C(100)); 74.69 (d, C(30));
64.81, 64.48 (2t, C(500), C(Fmoc)); 55.22 (q, CH3O-
DMT); 47.15 (d, C(Fmoc)); 43.78 (t, C(200)). HR-ESI+-
MS: m/z 832.3256 ([M+Na]+; C53H47NO7Na calcd
832.3250). IR (KBr): tmax 2933w, 2836w, 1735s, 1609s,
1543m, 1509s, 1446m, 1404w, 1374w, 1301w, 1250s,
1211s, 1177s, 1080s, 1036s, 903w, 830m, 790w, 758w,
741m, 700w, 585w, 543w.
4.2.27. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-b-D-ribofuranosyl-3-nitrobiphenyl (7f). Yellow foam
(576 mg, 0.93 mmol, 90%). Rf 0.3 (hexane/EtOAc
1
1:1 + 1% Et3N). H NMR (300 MHz, CDCl3): d 8.45
(t, J = 2.1, 1H, H(biph)); 8.24–8.7 (m, 1H, H(biph));
7.94–7.88 (m, 1H, H(biph)); 7.61 (t, J = 8.1, 3H,
H(biph)); 7.50 (m, 4H, H(biph), H(arom)); 7.41–7.19
(m, 7H, H(arom)); 6.84 (d, J = 8.9, 4H, H(arom));
5.26 (dd, J1 = 5.7, J2 = 10.0, 1H, H-C(100)); 4.51–4.45
(m, 1H, H-C(300)); 4.15–4.08 (m, 1H, H-C(400)); 3.80
(s, 6H, 2· CH3O-DMT); 3.40 (dd, J1 = 4.5, J2 = 9.8,
1H, H-C(500)); 3.32 (dd, J1 = 5.5, J2 = 9.8, 1H, H-
C(500)); 2.32 (ddd, J1 = 1.9, J2 = 5.7, J3 = 13.1, 1H,
H-C(200)); 2.15–2.04 (m, 1H, H-C(200)). 13C NMR
(75 MHz, CDCl3): d 158.48, 148.71, 144.80, 142.56,
142.45, 137.83, 135.97 (7s, C(biph), C(arom)); 132.94,
130.08, 129.70, 128.17, 127.85, 127.13, 126.82, 126.79
(8d, C(biph), C(arom)); 86.41 (d, C(400)); 86.25 (s,
C(Ph)3DMT); 79.56 (d, C(100)); 74.68 (d, C(30)); 64.41
(t, C(500)); 55.20 (q, CH3O-DMT); 43.89 (t, C(200)).
HR-ESI+-MS: m/z 640.2292 ([M+Na]+; C38H35NO7Na
calcd 640.2311). IR (KBr): tmax 3036w, 2932m, 2837w,
1735w, 1609m, 1583w, 1533s, 1510s, 1464m, 1446m,
1412w, 1350s, 1302m, 1251s, 1177s, 1156w, 1083s,
1034s, 953w, 902w, 877w, 830s, 805m, 903w, 877w,
830s, 806m, 792w, 756w, 744w, 727m, 703w, 683w,
636w, 585m.
4.3. General procedure for phosphitylation
Method A. To solutions of the DMT-protected nucleo-
sides 7 (1 equiv) in dry THF (25 ml/mmol) were added
N,N-diisopropylethylamine (3 equiv) followed by
2-cyanoethyl-diisopropylchlorophosphoramidite
(1.5
equiv) at room temperature. After 2 h (TLC control),
EtOAc was added and the organic phases were washed
with cold, sat. NaHCO3 solution. The combined aque-
ous phases were extracted with EtOAc. The combined
organic phases were dried (MgSO4), filtered, and con-

A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
6185
centrated in vacuo. Purification by FC (silica gel) yielded
the desired phosphoramidites 8.
(m, 12H, 4· CH3AiPr). 31P NMR (162 MHz, CDCl3):
d 148.23, 148.14. 13C NMR (75 MHz, CDCl3): d
158.49, 147.40, 147.35, 147.06, 144.90, 144.87, 142.92,
142.89, 137.94, 137.88, 136.13, 136.10, 136.05 (13s,
C(arom)); 130.19, 130.15, 128.32, 128.28, 127.80,
127.70, 127.38, 127.35, 126.85, 126.80, 126.76, 124.12
(12d, C(arom)); 117.54 (1s, CN); 113.10 (1d, C(arom));
86.23, 86.18, 85.92, 85.84 (4d, C(400)); 86.17 (s,
C(Ph)3DMT); 79.91, 79.84 (2d, C(100)); 76.37, 76.14,
75.89, 75.67 (4d, C(300)); 64.15, 64.11 (2t, C(500)); 58.47,
58.43, 58.22, 58.18 (4t, CH2–OP); 55.22 (1s, 2· AOCH3);
43.40, 43.29 (2t, C(200)); 43.18, 43.29 (2d, CHAiPr);
24.68, 24.59 24.54, 24.44 (4q, CH3-iPr); 20.45, 20.35,
20.28, 20.18 (4t, CH2–CN). HR-ESI+-MS: m/z 40.3401
([M+H]+; C47H52N3O8PNa calcd 840.3389). IR (KBr):
tmax 2968s, 2933m, 2838w, 2254w, 1608s, 1511s,
1464m, 1447m, 1397w, 1365m, 1343s, 1303m, 1252s,
1202w, 1179s, 1156w, 1111m, 1076s, 1034s, 1005s,
978s, 894w, 856w, 828s, 791m, 758m, 727m, 701m,
641w, 584w, 523w.
Method B. The DMT-protected nucleosides 7 (1 equiv)
and diisopropylammonium-1H-tetrazol-1-ide (2.2 equiv)
were dried by coevaporation with dry benzene and dis-
solved in dry CH2Cl2 (40 ml/mmol). N,N,N0,N0-tetraiso-
propyl-phosphordiamidite (2 equiv) was added and the
mixtures were stirred at room temperature for 16 h.
The mixtures were concentrated in vacuo. Purification
by FC (silica gel) yielded the desired phosphoramidites 8.
4.3.1. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-300-O-(2-cyanoethyl-N,N0-diisopropylaminophosphino)-
b-D-ribofuranosyl]-3,5-dinitrobiphenyl (8a). Method B.
Orange foam (104 mg, 0.12 mmol, 80%). Rf 0.45 (hex-
1
ane/EtOAc 7:3). H NMR (300 MHz, CDCl3): d 9.00
(t, 1H, J = 2.1, H-C(arom)); 8.76 (d, 2H, J = 2.1, H-
C(arom)); 7.68–7.57 (m, 4H, H-C(arom)); (m, 2H, H-
C(arom)); 7.41–7.33 (m, 4H, H-C(arom)); 7.31–7.18
(m, 3H, H-C(arom)); 6.82 (dd, 4H, J1 = 3.4, J2 = 8.9,
H-C(arom)), 5.26 (ddd, 1H, J1 = 1.9, J2 = 5.1,
J3 = 10.4, H-C(100)); 4.57 (dd, 1H, J1 = 6.0, J2 = 10.4,
H-C(300)); 4.34–4.24 (m, 1H, H-C(400)); 3.92–3.52 (m,
4H, CH2OP, 2· CHAiPr); 3.79, 3.78 (2s, 6H, 2· O-
CH3); 3.44–3.23 (m, 2H, 2· H-C(500)); 2.63 (t, 1H,
J = 6.3, CH2CN); 2.55–2.36 (m, 2H, CH2CN, H-C(200));
2.13–2.00 (m, 1H, H-C(200)); 1.28–1.06 (m, 12H,
4· CH3-iPr). 31P NMR (162 MHz, CDCl3): d 148.23,
148.20. 13C NMR (75 MHz, CDCl3): d 158.49, 158.47,
148.96, 144.85, 144.82, 144.62, 144.59, 144.11, 144.08,
136.06, 136.03, 135.99, 135.98, 135.50, 135.43 (15s,
C(arom)); 130.18, 130.14, 128.28, 128.24, 127.81,
127.26, 127.21, 127.18, 126.82 (9d, C(arom)); 117.58,
117.49 (2s, CN); 117.04, 117.02, 113.10 (3d, C(arom));
86.30, 86.25, 85.99, 86.91 (4d, C(400)); 86.17, 85.99 (2s,
C(Ph)3DMT); 79.74, 79.68 (2d, C(100)); 76.31, 76.08,
75.80, 75.58 (4d, C(400)); 64.09, 64.04 (2t, C(500)); 58.44,
58.40, 58.19, 58.14 (4t, CH2–OP); 55.25, 55.23 (2q, 2· –
OCH3); 43.44, 43.39 (2t, C(200)); 43.31, 43.27, 43.15,
43.11 (4d, CHAiPr); 24.69, 24.59, 24.56, 24.46, 24.44
(5q, CH3-iPr); 20.46, 20.37, 20.28, 20.19 (4t, CH2–CN).
HR-ESI+-MS: m/z 863.3451 ([M+H]+; C47H51N4O10P-
Na calcd 863.3421). IR (KBr): tmax 2968m, 2933m,
2254w, 1609m, 1545s, 1510s, 1464m, 1447w, 1397w,
1347s, 1301m, 1251s, 1202w, 1179s, 1156w, 1127w,
1077s, 1035s, 978m, 908w, 830m, 791w, 776w, 756w,
730m, 704w, 585w, 525w.
4.3.3. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-300-O-(2-cyanoethyl-N,N0-diisopropylaminophosphino)-
b-D-ribofuranosyl]-3-methoxybiphenyl (8c). Method A.
Colorless foam (606 mg, 0.75 mmol, 84%). Rf 0.30,
1
0.35 (hexane/EtOAc 8:2). H NMR (300 MHz, CDCl3):
d 7.55 (d, 2H, J = 8.1, H-C(arom)); 7.52–7.45 (m, 4H,
H-C(arom)); 7.41–7.10 (m, 10H, H-C(arom)); 6.89
(ddd, 1H, J1 = 0.8, J2 = 2.5, J3 = 8.2, H-C(arom)); 6.82
(dd, 4H, J1 = 3.8, J2 = 9.0, H-C(arom)); 5.21 (ddd, 1H,
J1 = 1.9, J2 = 5.0, J3 = 10.5, H-C(100)); 4.54 (dd, 1H,
J1 = 5.8, J2 = 10.7, H-C(300)); 4.29–4.21 (m, 1H, H-
C(400)); 3.90–3.50 (m, 4H, CH2OP, 2· CHAiPr); 3.86,
3.78, 3.77 (3s, 9H, 3· O-CH3); 3.39–3.22 (m, 2H, 2· H-
C(500)); 2.62 (t, 1H, J = 6.6, CH2CN); 2.47 (t, 1H,
J = 6.6, CH2CN); 2.46–2.31 (m, 1H, H-C(200)); 2.14–
2.01 (m, 1H, H-C(200)); 1.22–1.04 (m, 12H, 4· CH3-
iPr). 31P NMR (162 MHz, CDCl3): d 148.20, 148.00.
13C NMR (75 MHz, CDCl3): d 159.92, 158.43, 144.91,
144.89, 142.50, 142.48, 140.97, 140.93, 140.35, 140.29,
136.14, 136.10 (12s, C(arom)); 130.18, 130.17, 130.14,
129.74, 128.31, 128.27, 127.78, 127.14, 127.12, 126.76,
126.72, 126.52, 119.61 (13d, C(arom)); 117.55, 117.50
(2s, CN); 113.07, 112.80, 112.65 (3d, C(arom)); 86.11,
86.05, 85.78, 85.70 (4d, C(400)); 86.08 (s, C(Ph)3DMT);
80.13, 80.06 (2d, C(100)); 76.38, 76.15, 75.96, 75.73
(4d, C(300)); 64.21, 64.17 (2t, C(500)); 58.46, 58.44, 58.21,
58.19 (4t, CH2–OP); 55.31, 55.22, 55.20 (3s, 3·
–OCH3); 43.33 (t, C(200)); 43.29, 43.25, 43.12, 43.08 (4d,
CHAiPr); 24.69, 24.67, 24.59, 24.58, 24.51, 24.42 (6q,
CH3-iPr); 20.41, 20.32, 20.25, 20.16 (4t, CH2–CN).
HR-ESI+-MS: m/z 803.3833 ([M+H]+; C48H55N2O7PNa
calcd 803.3825). IR (KBr): tmax 2967m, 2933m, 2837w,
2253w, 1609s, 1585m, 1568w, 1510s, 1483m, 1465m,
1447m, 1398w, 1365m, 1298m, 1252s, 1221m, 1202w,
1179s, 1157m, 1126w, 1076s, 1054s, 1033s, 978s, 879w,
829s, 790m, 755m, 727m, 699m, 641w, 584w, 523w.
4.3.2. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-300-O-(2-cyanoethyl-N,N0-diisopropylaminophosphino)-
b-D-ribofuranosyl]-4-nitrobiphenyl (8b). Method A. Slight-
ly yellow foam (242 mg, 0.30 mmol, 74%). Rf 0.4 (hex-
1
ane/EtOAc 8:2). H NMR (300 MHz, CDCl3): d 8.29
(d, 2H, J = 8.9, H-C(arom)); 7.73 (d, 2H, J = 8.9, H-
C(arom)); 7.62–7.45 (m, 6H, H-C(arom)); 7.41–7.17
(m, 7H, H-C(arom)); 6.85–6.78 (m, 4H, H-C(arom));
5.27–5.19 (m, 1H, H-C(100)); 4.60–4.51 (m 1H, H-
C(300)); 4.31–4.22 (m, 1H, H-C(400)); 3.91–3.52 (m, 4H,
CH2OP, 2· CHAiPr); 3.79, 3.78 (2s, 6H, 2· OACH3);
3.41–3.23 (m, 2H, 2· H-C(500)); 2.63 (t, 1H, J = 6.4,
CH2CN); 2.47 (t, 1H, J = 6.4, CH2CN); 2.52–2.34 (m,
1H, H-C(200)); 2.13–2.00 (m, 1H, H-C(200)); 1.32–1.07
4.3.4. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-300-O-(2-cyanoethyl-N,N0-diisopropylaminophosphino)-
b-D-ribofuranosyl]-4-methoxybiphenyl (8d). Method A.
Colorless foam (273 mg, 0.34 mmol, 64%). Rf 0.4 (hex-
1
ane/EtOAc 8:2). H NMR (300 MHz, CDCl3): d 7.55–

6186
A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
7.43 (m, 8H, H-C(arom)); 7.41–7.33 (m, 4H,
H-C(arom)); 7.31–7.16 (m, 3H, H-C(arom)); 6.97 (d,
2H, J = 8.7, H-C(arom)); 6.85–6.78 (m, 4H, H-C(arom));
5.24–5.16 (m, 1H, H-C(100)); 4.59–4.49 (m 1H,
H-C(300)); 4.29–4.21 (m, 1H, H-C(400)); 3.91–3.51 (m,
4H, CH2OP, 2· CHAiPr); 3.84, 3.78, 3.77 (3s, 9H,
3· O-CH3); 3.38–3.22 (m, 2H, 2· H-C(500)); 2.61 (t, 1H,
J = 6.6, CH2CN); 2.47 (t, 1H, J = 6.6, CH2CN); 2.46–
2.31 (m, 1H, H-C(200)); 2.14–2.01 (m, 1H, H-C(200));
1.31–1.04 (m, 12H, 4· CH3-iPr). 31P NMR (162 MHz,
CDCl3): d 148.20, 147.98. 13C NMR (75 MHz, CDCl3):
d 159.12, 158.42, 144.91, 140.10, 140.07, 140.04, 136.14,
136.10, 135.51, 133.48 (10s, C(arom)); 130.13, 128.30,
128.26, 128.06, 127.75, 126.72, 126.68, 126.63, 126.61,
126.51 (10d, C(arom)); 117.48, 117.45 (2s, CN); 114.18,
113.06 (2d, C(arom)); 86.09, 86.06, 85.99, 85.65 (4d,
C(400)); 86.08 (s, C(Ph)3DMT); 80.13, 80.07 (2d, C(100));
76.39, 76.16, 75.97, 75.76 (4d, C(300)); 64.23, 64.18 (2t,
C(500)); 58.46, 58.44, 58.21, 58.17 (4t, CH2–OP); 55.31,
55.19 (2s, 3· –OCH3); 43.26 (t, C(200)); 43.14, 43.10 (2d,
CHAiPr); 24.66, 24.55 24.48, 24.39 (4q, CH3-iPr);
20.41, 20.29, 20.23, 20.13 (4t, CH2–CN). HR-ESI+-MS:
m/z 803.3844 ([M+H]+; C48H55N2O7PNa calcd
803.3825). IR (KBr): tmax 2967m, 2932m, 2837w,
2253w, 1609s, 1583w, 1509s, 1464m, 1446w, 1397w,
1365w, 1294m, 1250s, 1178s, 1156m, 1076s, 1037s,
1001m, 977m, 893w, 823s, 791w, 755w, 727w, 702m,
635w, 583w, 524w.
1126w, 1075m, 1030s, 978m, 882w, 830m, 808m, 791w,
766w, 756w, 727w, 702w, 584w, 524w.
4.3.6. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-300-O-(2-cyanoethyl-N,N0-diisopropylaminophosphino)-
b-D-ribofuranosyl]-3-nitrobiphenyl (8f). Method A Color-
less foam (537 mg, 0.66 mmol, 89%). Rf 0.45, 0.50
(hexane/EtOAc 7:3). 1H NMR (400 MHz, CDCl3): d
8.49–8.43 (m, 1H, H-C(arom)); 8.24–8.15 (m, 1H, H-
C(arom)); 7.96–7.87 (m, 1H, H-C(arom)); 7.67–7.44
(m, 7H, H-C(arom)); 7.42–7.33 (m, 4H, H-C(arom));
7.33–7.17 (m, 3H, H-C(arom)); 6.88–6.77 (m, 4H,
H-C(arom)); 5.24 (ddd, J1 = 1.9, J2 = 5.0, J3 = 10.4,
1H, H-C(100)); 4.62–4.52 (dd, J1 = 5.7, J2 = 10.8, 1H,
H-C(300)); 4.32–4.24 (m, 1H, H-C(400)); 3.93–3.53 (m,
4H, CH2OP, 2· CHAiPr), 3.80, 3.79 (2s, 6H, 2· O-
CH3); 3.43–3.24 (m, 2H, H-C(500)); 2.64 (dt, J1 = 0.4,
J2 = 6.3, 1H, CH2CN); 2.54–2.35 (m, 2H, CH2CN,
H-C(200)); 2.15–2.03 (m, 1H, H-C(200)); 1.23–1.06 (m,
12H, 4· CH3-iPr). 31P NMR (162 MHz, CDCl3): d
148.22, 148.09. 13C NMR (75 MHz, CDCl3): d 158.42,
148.71, 144.85, 144.82, 142.61, 142.58, 142.39, 142.36,
137.84, 137.79, 136.08, 136.05, 136.00 (13s, C(arom));
132.97, 130.15, 130.12, 129.70, 128.27, 128.23, 127.77,
127.13, 127.09, 126.86, 126.77, 126.74, 121.98, 121.85
(14d, C(arom)); 117.54, 117.48 (2s, CN); 113.05 (d,
C(arom)); 86.19, 86.11, 85.86, 85.78 (4d, C(400)); 86.13,
86.08 (2s, C(Ph)3DMT); 79.92, 79.85 (2d, C(100)); 76.33,
76.09, 75.86, 75.64 (4d, C(300)); 64.13, 64.08 (2t, C(500));
58.42, 58.39, 58.17, 58.14 (4t, CH2–OP); 55.21, 55.20
(2q, CH3O-DMT); 43.39, 43.33 (2t, C(200)); 43.28,
43.23, 43.11, 43.06 (4d, CHAiPr); 24.67, 24.58, 24.51,
24.42 (4q, CH3-iPr); 20.42, 20.33, 20.25, 20.15 (4t,
CH2–CN). HR-ESI+-MS: m/z 818.3594 ([M+H]+;
C47H52N3O8PNa calcd 818.3570). IR (KBr): tmax
2967m, 2932m, 2253w, 1737w, 1609m, 1584w, 1533s,
1510s, 1464m, 1446w, 1397w, 1351s, 1302w, 1252s,
1201w, 1179s, 1156w, 1076m, 1035s, 978m, 878w,
830m, 806w, 791w, 727m, 704w, 640w, 585w, 522w.
4.3.5. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-300-O-(2-cyanoethyl-N,N0-diisopropylaminophosphino)-
b-D-ribofuranosyl]-3,4-dimethoxybiphenyl (8e). Method
A. Colorless foam (577 mg, 0.69 mmol, 84%). Rf 0.55,
1
0.50 (hexane/EtOAc 6:4). H NMR (300 MHz, CDCl3):
d 7.55–7.44 (m, 6H, H-C(arom)); 7.42–7.34 (m, 4H,
H-C(arom)); 7.32–7.09 (m, 5H, H-C(arom)); 6.94 (d,
1H, J = 8.3, H-C(arom)); 6.82 (dd, 4H, J1 = 3.7,
J2 = 8.9, H-C(arom)); 5.21 (ddd, 1H, J1 = 2.1, J2 = 5.0,
J3 = 10.5, H-C(100)); 4.55 (dd, 1H, J1 = 6.0, J2 = 10.8,
H-C(300)); 4.29–4.22 (m, 1H, H-C(400)); 3.95, 3.92, 3.87,
3.77 (4s, 12H, 4· O-CH3); 3.92–3.50 (m, 4H, CH2OP,
2· CHAiPr); 3.40–3.21 (m, 2H, 2· H-C(500)); 2.62 (t,
J = 6.3, 1H, CH2CN); 2.50–2.32 (m, 2H, CH2CN,
H-C(200)); 2.15–2.02 (m, 1H, H-C(200)); 1.22–1.05 (m,
12H, 4· CH3-iPr). 31P NMR (162 MHz, CDCl3): d
148.18, 148.00. 13C NMR (75 MHz, CDCl3): d 158.42,
149.13, 148.58, 148.57, 144.93, 144.90, 140.34, 140.32,
140.26, 136.16, 136.13 136.10, 136.08, 134.00, 133.96
(15s, C(arom)); 130.18, 130.14, 128.31, 128.27, 127.78,
126.80, 126.78, 126.71, 126.54, 119.32 (10d, C(arom));
117.55, 117.50 (2s, CN); 113.55, 111.45, 110.38 (3d,
C(arom)); 86.08, 86.06, 85.76, 85.69 (4d, C(400)); 86.07,
86.04 (2s, C(Ph)3DMT); 80.15, 80.07 (2d, C(100)); 76.37,
76.14, 75.93, 75.72 (4d, C(300)); 64.18, 64.14 (2t, C(500));
58.46, 58.43, 58.21, 58.18 (4t, CH2–OP); 55.99, 55.95,
55.21 (3s, 4· –OCH3); 43.39, 43.33 (2t, C(200)); 43.29,
43.25, 43.13, 43.09 (4d, CHAiPr); 24.69, 24.67, 24.59,
24.58, 24.42, 24.41 (6q, CH3-iPr); 20.41, 20.32, 20.25,
20.16 (4t, CH2–CN). HR-ESI+-MS: m/z 855.3754
([M+Na]+; C49H57N2O8PNa calcd 855.3750). IR
(KBr): tmax 2967m, 2934m, 2837w, 2253w, 1609m,
1590w, 1528w, 1508s, 1465m, 1447m, 1398w, 1365w,
1327w, 1302m, 1252s, 1219m, 1202w, 1176s, 1144m,
4.3.7. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-300-O-(2-cyanoethyl-N,N0-diisopropylaminophosphino)-
b-D-ribofuranosyl]-3-Fmoc-aminobiphenyl (8h). Method
B. Colorless foam (537 mg, 0.66 mmol, 89%). Rf 0.3
(hexane/EtOAc 7:3 + 1% Et3N). 1H NMR (300 MHz,
CDCl3): d 7.77 (d, 2H, J = 7.4, H(arom)); 7.65–7.18
(m, 23H, H(arom)); 6.85–6.73 (m, 5H, H(arom), –NH–
); 5.21 (ddd, 1H, J1 = 2.1, J2 = 4.9, J3 = 10.4, H-C(100));
4.58–4.50 (m, 3H, H-C(300), H-Fmoc); 4.31–4.22 (m,
2H, H-C(400), H-Fmoc); 3.90–3.51 (m, 4H, CH2OP,
2· CHAiPr); 3.77, 3.76 (2s, 6H, 2· CH3O-DMT); 3.39–
3.22 (m, 2H, H-C(500)); 2.62 (t, 1H, J = 6.4, CH2CN);
2.50–2.31 (m, 2H, H-C(200), CH2CN); 2.14–2.01 (m,
1H, H-C(200)); 1.28–1.04 (m, 12H, 4· CH3-iPr). 31P
NMR (162 MHz, CDCl3): d 148.23, 148.02. 13C NMR
(75 MHz, CDCl3): d 158.46, 153.40, 144.89, 143.74,
141.98, 141.95, 141.38, 141.15, 141.12, 139.93, 139.87,
138.15, 136.17, 136.14, 136.12 (15s, C(arom)); 130.17,
129.47, 128.35, 128.30, 127.88, 127.14, 127.10, 126.77,
126.74, 126.54, 124.96, 122.40, 120.06, 117.53 (14d,
C(arom));, 117.48 (s, CN); 113.11 (d, C(arom)); 86.14
(s, C(Ph)3DMT); 86.11, 86.04, 85.79, 85.71 (4d, C(40));
80.09, 80.02 (2d, C(100)); 76.39, 76.15, 75.96, 75.73 (4d,

A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
6187
C(300)); 66.88, 64.23, 64.17 (3t, C(500), C(Fmoc)); 58.47,
58.22 (2t, CH2OP); 55.23, 5.22 (2q, CH3O-DMT);
47.18 (d, C(Fmoc)); 43.34 (t, C(200)), 43.30, 43.25,
43.18, 43.13 (4d, CHAiPr); 24.68, 24.58, 24.53, 24.43
(4q, CH3-iPr); 20.42, 20.33, 20.26, 20.17 (4t, CH2–CN).
HR-ESI+-MS: m/z 1032.4348 ([M+Na]+; C62H64N3O8P-
Na calcd 1032.4328). IR (KBr): tmax 3036w, 2965m,
2930m, 2836w, 2252w, 1735s, 1608s, 1543m, 1509s,
1463m, 1446m, 1397w, 1364w, 1317m, 1301m, 1250s,
1209s, 1179s, 1155m, 1075s, 1036s, 977m, 889w, 830m,
790w, 758m, 740s, 701m, 641w, 621w, 585w, 543w,
524w, 428w.
ane (200 ml) was added to the residue and the mixture
was heated to the reflux for 30 min. The mixture was
slowly cooled to ꢀ78 ꢁC and the precipitate was filtered
off, washed with cold hexane, and dried in vacuo to yield
the desired compound (1.58 g, 5.4 mmol, 54%) as a
1
brownish powder. H NMR (300 MHz, CDCl3): d 9.11
(t, 1H, J = 2.26, H-4); 8.93 (d, 2H, J = 2.26, H-2, H-5);
1.40 (s, 12H, 4· CH3). 11B-MMR (128 MHz, CDCl3):
d 32.92 (s). 13C NMR (101 MHz, CDCl3): d 148.17 (s,
C(arom)); 134.41, 120.99 (2d, C(arom)); 85.48 (s,
2· C(CH3)2); 24.85 (q, 4· CH3). HR-EI-MS: m/z
294.1035 (M+; C12H15BN2O6 calcd 294.1023). IR (neat):
tmax 3108w, 2984w, 1627w, 1586w, 1542m, 1468w,
1372w, 1336s, 1265w, 1209w, 1168w, 1136m, 1074w,
968w, 918w, 846m, 812w, 728m, 687s, 661w, 640w.
4.3.8. 40-[200-Deoxy-500-O-(4,40-dimethoxytriphenylmeth-
yl)-300-O-(2-cyanoethyl-N,N0-diisopropylaminophosphino)-
b-D-ribofuranosyl]-4-Fmoc-aminobiphenyl (8g). Method
A. (70 mg, 0.07 mmol, 58%) as a colorless foam. Rf 0.3
(hexane/EtOAc 7:3 + 1% Et3N). 1H NMR (300 MHz,
CDCl3): d 7.78 (d, 2H, J = 7.4, H(arom)); 7.63 (d, 2H,
J = 7.4, H(arom)); 7.56–7.16 (m, 21H, H(arom)); 6.85–
6.77 (m, 4H, H(arom)); 6.72 (s, 1H, –HN–); 5.21 (ddd,
1H, J1 = 2.1, J2 = 5.0, J3 = 10.5, H-C(100)); 4.59–4.50
(m, 3H, H-C(300), H-Fmoc); 4.32–4.22 (m, 2H, H-C(400),
H-Fmoc); 3.90–3.51 (m, 4H, CH2OP, 2· CHAiPr);
3.78, 3.77 (2s, 6H, 2· CH3O-DMT); 3.39–3.22 (m, 2H,
H-C(500)); 2.62 (t, 1H, J = 6.6, CH2CN); 2.49–2.31 (m,
2H, H-C(200), CH2CN); 2.13–2.00 (m, 1H, H-C(200));
1.29–1.06 (m, 12H, 4· CH3-iPr). 31P NMR (162 MHz,
CDCl3): d 148.23, 148.01. 13C NMR (75 MHz, CDCl3):
d 158.46, 153.37, 144.94, 143.76, 141.40, 140.62, 140.59,
139.77, 139.71, 136.98, 136.26, 136.17, 136.15, 136.13
(14s, C(arom)); 130.19, 130.16, 128.34, 128.30, 127.81,
127.63, 127.15, 126.74, 126.59, 124.95, 120.07, 119.14
(12d, C(arom)); 117.52, 117.48 (2s, CN); 113.10 (d,
C(arom)); 86.14, 86.78 (2s, C(Ph)3DMT); 86.11, 85.71
(2d, C(40)); 80.13, 80.07 (2d, C(100)); 77.23, 76.19, 75.99,
75.77 (4d, C(300)); 66.90, 64.25, 64.20 (3t, C(500),
C(Fmoc)); 58.47, 58.24 (2t, CH2OP); 55.22 (q, CH3O-
DMT); 47.18 (d, C(Fmoc)); 43.19 (t, C(200)), 43.18,
43.13 (2d, CHAiPr); 24.68, 24.59, 24.52, 24.43 (4q,
CH3-iPr); 20.43, 20.33, 20.26, 20.17 (4t, CH2–CN).
HR-ESI+-MS: m/z 1032.4283 ([M+Na]+; C62H64N3O8P-
Na calcd 1032.4328). IR (KBr): tmax 3035w, 2965m,
2930m, 2836w, 2252w, 1734m, 1608m, 1534m, 1509s,
1463w, 1448m, 1397w, 1364w, 1317m, 1301m, 1251s,
1214s, 1179s, 1156m, 1074s, 1054s, 1033s, 1003m,
977m, 902w, 824m, 791w, 758m, 740m, 703m, 620w,
584w, 524w, 427w.
4.3.10. Oligonucleotide synthesis. Oligonucleotide syn-
thesis was performed on an Expedite 8909 (Applied Bio-
systems) or a Gene Assembler Plus (Pharmacia) DNA
synthesizer on a 1.0 or 1.3 lmol scale using standard
phosphoramidite chemistry and phosphoramidites of
the natural nucleosides (Glen Research) as well as phos-
phoramidites 8a, c, e, f. 5-(ethylthio)-1H-tetrazole
(0.25 M in CH3CN) were used as the coupling reagent
and 3% dichloroacetic acid in dichloroethane was used
for the detritylation step. After synthesis, the oligonucle-
otides were detached and deprotected in concd. ammo-
nia (55 ꢁC, 16 h). Crude oligonucleotides were purified
¨
by RP-HPLC on an Akta P-900 (Pharmacia) with a
Source 15RPC ST 4.6/100 column (Pharmacia). A gradi-
ent of the following two solutions was used for elution:
A: 0.1 M triethylammonium acetate (TEAA) in H2O; B:
0.1 M TEAA in 80% AcCN. The integrity of the oligo-
nucleotides was confirmed with ESIꢀ-MS spectroscopy.
Acknowledgments
We thank the Swiss National Science Foundation
(Grant No. 200020-107692) and the Roche Research
Foundation (Grant No. 2004-144) for financial support
of this project.
References and notes
1. (a) Franchetti, P.; Cappellacci, L.; Griffantini, M.; Barzi,
A.; Nocentini, G.; Yang, H. Y.; O’Connor, A.; Jayaram,
H. N.; Carrell, C.; Goldstein, B. M. J. Med. Chem. 1995,
38, 3829–3837; (b) Walker, J. A.; Liu, W.; Wise, D. S.;
Drach, J. C.; Townsend, L. B. J. Med. Chem. 1998, 41,
1236–1241.
2. (a) Kim, T. W.; Kool, E. T. J. Org. Chem. 2005, 70, 2048–
2053; (b) Guckian, K. M.; Schweitzer, B. A.; Ren, R. X.-
F.; Sheils, C. J.; Paris, P. L.; Tahmassebi, D. C.; Kool, E.
T. J. Am. Chem. Soc. 2000, 122, 2213–2222.
3. Kool, E. T. Curr. Opin. Chem. Biol. 2000, 4, 602–608.
4. Matray, T. J.; Kool, E. T. Nature 1999, 399, 704–708.
5. (a) Berger, M.; Ogawa, A. K.; McMinn, D. L.; Wu, Y. Q.;
Schultz, P. G.; Romesberg, F. E. Angew. Chem. Int. Ed.
2000, 39, 2940–2942; (b) Berger, M.; Luzzi, S. D.; Henry,
A. A.; Romesberg, F. E. J. Am. Chem. Soc. 2002, 124,
1222–1226;; (c) McMinn, D. L.; Ogawa, A. K.; Wu, Y.;
Liu, J.; Schultz, P. G.; Romesberg, F. E. J. Am. Chem.
Soc. 1999, 121, 11585–11586; (d) Ogawa, A. K.; Wu, Y.
4.3.9. 3,5-Dinitrophenyl-pinacolboronate. A solution of
1-Iodo-3,5-dinitrobenzene (2.94 g, 10.0 mmol), pin-
acolborane (2.2 ml, 15.0 mmol), Et3N (4.3 ml,
30.0 mmol), and PdCl2(dppf) (245 mg, 3 mol%) in dry
dioxane (40 ml) was stirred at 85 ꢁC over 16 h. After
cooling to room temperature, the solution was poured
into 2 M NaOH solution (400 ml) and washed with
CH2Cl2 (3 · 100 ml). The combined organic phases were
extracted with 2 M NaOH solution (2 · 100 ml). The
combined basic extracts were cooled to 0 ꢁC and adjust-
ed to pH 3 with 85% H3PO4. The acidic solution was
extracted with t-BuOMe (4 · 100 ml). The combined
organic phases were washed with brine (100 ml), dried
over MgSO4, filtered, and concentrated in vacuo. Hex-

6188
A. Zahn, C. J. Leumann / Bioorg. Med. Chem. 14 (2006) 6174–6188
Q.; McMinn, D. L.; Liu, J.; Schultz, P. G.; Romesberg, F.
9. (a) Wichai, U.; Woski, S. A. Bioorg. Med. Chem. Lett.
1998, 8, 3465–3468; (b) Wichai, U.; Woski, S. A. Org.
Lett. 1999, 8, 1173–1175.
10. Deriaz, R. E.; Overend, W. G.; Stacey, M.; Teece, E. G.;
Wiggins, L. F. J. Chem. Soc. 1947, 1879–1883.
11. Walker, J. A.; Chen, J. J.; Wise, D. S.; Townsend, L. B.
J. Org. Chem. 1996, 61, 2219–2221.
12. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 9550–9561.
13. Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y.
J. Org. Chem. 2000, 65, 164–168.
14. Augeri, D. J.; O’Connor, S. J.; Janowick, D.; Szczepan-
kiewicz, B.; Sullivan, G.; Larsen, J.; Kalvin, D.; Cohen, J.;
Devine, E.; Zhang, H.; Cherian, S.; Saeed, B.; Ng, S.-C.;
Rosenberg, S. J. Med. Chem 1998, 41, 4288–4300.
E. J. Am. Chem. Soc. 2000, 122, 3274–3287; (e) Tae, E. L.;
Wu, Y.; Xia, G.; Schultz, P. G.; Romesberg, F. E. J. Am.
Chem. Soc. 2001, 123, 7439–7440; (f) Yu, C.; Henry, A. A.;
Romesberg, F. E.; Schultz, P. G. Angew. Chem. Int. Ed.
2002, 41, 3841–3844.
6. (a) Brotschi, C.; Leumann, C. J. Angew. Chem. Int.
Ed. 2003, 42, 1655–1658; (b) Brotschi, C.; Mathis,
G.; Leumann, C. J. Chem. Eur. J. 2005, 11, 1911–
1923.
7. (a) Meggers, E.; Michel-Beyerle, M. E.; Giese, B. J. Am.
Chem. Soc. 1998, 120, 12950–12955; (b) Giese, B. Acc.
Chem. Res. 2000, 33, 631–636.
´ˇ ´
8. Hocek, M.; Pohl, R.; Klepetarova, B. Eur. J. Org. Chem.
2005, 4525–4528.