Synthesis of the amidite reagent to built bipyridine units into DNA backbone

Article abstract of DOI:10.3987/COM-04-10258

A new amidite reagent (9) containing 6,6′-bis(acylamino)-2,2′-bipyridine unit was synthesized in moderate yields by a dependable eight step procedure. The unit should work as a metal ion-directed conformational modulator when it is built into the backbone

Full text of DOI:10.3987/COM-04-10258

HETEROCYCLES, Vol. 65, No. 2, 2005
293
HETEROCYCLES, Vol. 65, No. 2, 2005, pp. 293 - 301
Received, 22nd October, 2004, Accepted, 15th December, 2004, Published online, 17th December, 2004
SYNTHESIS OF THE AMIDITE REAGENT TO BUILT BIPYRIDINE
UNITS INTO DNA BACKBONE
Toshihiro Ihara,a, c* Yoshinori Shirasaka,a Yoshinobu Sato,a Yusuke Kitamura,a
Kenji Okada,a Masato Tazaki,b and Akinori Jyoa
a Department of Applied Chemistry and Biochemistry, Faculty of Engineering,
Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan, e-mail:
toshi@chem.kumamoto-u.ac.jp
b
General Education, Faculty of Engineering, Sojo University, 4-22-1 Ikeda,
Kumamoto 860-0082, Japan
c
PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi,
Saitama 332-0012, Japan
Abstract – A new amidite reagent (9) containing 6,6’-bis(acylamino)-2,2’-
bipyridine unit was synthesized in moderate yields by a dependable eight step
procedure. The unit should work as a metal ion-directed conformational
modulator when it is built into the backbone of synthetic DNAs.
INTRODUCTION
Various functional groups have been chemically attached to biomolecules to create bioconjugates with
desired functions.1 DNA is an attractive material for making functional molecules because of its
programmability for molecular recognition, ease of chemical modification, and moderate chemical
stability. The development of genome chemistry has made it possible to synthesis a large number of DNA
conjugates, which have been applied not only in the area of genomics2 but also in engineering works,3
such as in making unique nanostructures.
Recently, functional DNA molecules such as deoxyribozymes,4 aptamers,5 and antisense DNAs6 have
been extensively studied. Prescript higher ordered structures are critical for these single stranded-DNAs
to express their right function. Therefore, the techniques to control their structures reversibly should be

294
HETEROCYCLES, Vol. 65, No. 2, 2005
useful for modulation of the corresponding functions. If the chemical groups that changes their
conformation by certain stimuli are built into the backbone of the functional DNAs, we could regulate the
functions secondarily by controlled conformational change of the DNAs. The strategy is general in the
sense that it targets the conformation rather than each particular function.
Here we present the synthesis of the amidite reagent carrying the ligand, 6,6’-bis(acylamino)-2,2’-
bipyridine unit. We can build the ligand into any position in DNA backbone with this amidite reagent
using automated DNA synthesizer. This ligand was reported to form square planar complex with Cu(II)
or Co(II) to yield cisoid conformation.7 It means that we could bend the DNA by adding certain metal
ions through transoid-cisoid transformation. That is, the unit should work as a metal ion-directed
conformation modulator of DNA (Figure 1).
H
N
H
N
O
O
O
O
N
N
O
N
O
N
O
O
N
H
N
H
transoid, linear state
cisoid, bent state
Figure 1. Metal ion-directed conformational modulater of DNA
RESULTS AND DISCUSSION
The 6,6’-bis(acylamino)-2,2’-bipyridine-based amidite reagent was synthesized according to Scheme.
Generally a diol is the key compound when one designs the synthetic scheme of an amidite reagent. One
of its hydroxyl groups is tritylated by 4,4’-dimethoxytrityl chloride, and then the other is phosphitylated
by chloro(diisopropylamino)(b-cyanoethoxy)phosphine to form the desired structure of amidite reagent
directly used for an automated DNA synthesizer. Here the bipy diol (7) was synthesized as the key
compound by acetoxyacetylation of the diaminobipyridine (5) and subsequent hydrolysis.
The diaminobipyridine (5) was prepared in four steps from 2,6-dibromopyridine (1) basically according
to the procedures previously described.8, 9 The intermediates (2, 3, and 4) were obtained in reasonable
yields, 50, 96, and 90 %, respectively. The procedure for the synthesis of 5 from 4 was modified from that
of the literature.9 We used a reductant tri-n-butylphosphine in MeOH-H2O (7:3) instead of phosphonium
salt.10 It improved significantly the yield, up to 83 %, even under the mild conditions (room temperature,
5 h).

HETEROCYCLES, Vol. 65, No. 2, 2005
295
NHNH2
NH2
NH2
N3
N3
Br
Br
Br
N
N
N
N
N
N
NaNO /HCl
N
N
nBu P
2
NH NH
nBuLi/CuCl
3
2
2
2
Et O
2
MeOH/H O
2
N
Br
NHNH2
1
2
3
4
5
H
N
H
N
Cl
OH
O
OAc
OAc
OAc
K CO
2 3
N
N
N
N
O
O
O
H O/MeOH
2
Pyridine
O
OH
N
H
N
H
6
7
Cl
O
H
N
H
N
P
N
CN
DMTr
DMTr
O
O
DMTr-Cl
Pyridine
i-Pr
i-Pr
N
N
O
N
N
O
O
CH Cl , (iPr) NEt
2
2
2
O
O
O
OH
N
H
P
N
CN
N
H
i-Pr
i-Pr
8
9
Scheme. Synthesis of amidite (9)
The diaminobipyridine (5) was acylated with acetoxyacetyl chloride in pyridine to afford the diacetate
ester (6). The compound (6) was obtained as a white powder in 79 % yield. It was then hydrolyzed
quantitatively in 10 % K2CO3 aq-MeOH solution to afford the diol (7) as a white powder.
Both of the hydroxyl groups in 7 are the primary. They are supposed to have the same reactivity during
the tritylation with 4,4’-dimethoxytrityl chloride. Therefore, to obtain the monotritylated alcohol (8) in a
good yield, the reaction conditions such as feeding ratio of 7 and 4,4’-dimethoxytrityl chloride, reaction
time, and temperature were critical. The crude product was chromatographed on a silica gel column with
dichloromethane-diethylamine (100:1) to give 8 as a pale yellow powder with no decomposition during
the chromatography. The reaction at 60°C for 1 h gave 8 in 56 % yield without significant formation of
the bistritylated byproduct even when about more than twice moles of 4,4’-dimethoxytrityl chloride was
used. Elongation of the reaction time up to 24 h under the same conditions resulted in a decrease in the
yield of 8 and the formation of the bistritylated byproduct only in ca. 20 % yield. The reaction rate was
rather slower than that expected from the literatures.11 The characteristics of the reaction show the
reaction is more chemoselective for the formation of 8 than the initially expected, owing to some
inhibition of the second tritylation. The bipyridyl moiety of the monotritylated product (8) is much more
basic than the solvent pyridine, because the protonated form is stabilized by making intramolecular

296
HETEROCYCLES, Vol. 65, No. 2, 2005
hydrogen bonding with another nitrogen, N-HÛN, in its cisoid conformation.12 Therefore, the hydrogen
chloride liberated during the reaction may form a salt preferentially with the bipyridyl moiety of 8.
According to the density functional theoretical method (B3LYP/6-31G(d)), dihedral angles of N-C-C-N
in bipyridine center were calculated to be 180° (transoid) and 6.8° (cisoid) for 8 and protonated 8,
respectively. That is, 7 in transoid conformation reacts with a trityl chloride to form 8 and then 8 would
flip its conformation to take cisoid form with the assistance of the protonation. The cationic bipyridyl
moiety and cisoid conformation of the protonated 8 may prevent the further attack of the reagent DMTr+
by electrostatic repulsion and steric hindrance, respectively.
The amidite (9) was prepared by phosphitylation of 8 with chloro(diisopropy1amino)-(b-
cyanoethoxy)phosphine. It was obtained as a white powder in 55 % yield. This yield is lower than those
of the corresponding reactions in the literatures.11 The steric hindrance should decrease the rate of
phosphitylation. The long reaction time and the low solubility of 8 in the solvent (dichloromethane)
would make 9 and chloro(diisopropy1amino)(b-cyanoethoxy)phosphine easy to be degraded by residual
water.
1
13
The structures of the new compounds (6 – 9) obtained in this study were confirmed fully by H and C
NMR, IR spectra, and elemental analyses. Thus, we could prepare the target amidite (9) in reasonable
yield with a sufficient purity for the use to a DNA synthesizer.
EXPERIMENTAL
Dibromobipyridine (2)8 2,6-dibromopyridine (1) (4.02 g, 17.0 mmol) was suspended in anhydrous ether
(20 mL) at -70°C (acetone-dry ice) under an atmosphere of Argon. To the mixture, a hexane solution of
n-butyllithium (1.6 M, 13 mL, 20.8 mmol) was added slowly via an addition funnel to keep the
temperature. The suspension gradually dissolved and the color of the solution turned into yellow.
Anhydrous copper dichloride (1.14 g, 8.5 mmol) was then added into the solution with vigorous stirring.
After 30 min the dry air was infused into the flask, and the mixture was stirred again for 15 min. After the
color of the solution turned into green, 20 mL of 6 M hydrochloric acid was added to the solution. The
resulting white solid was filtered and washed with 0.5 M hydrochloric acid. The product was used for the
next step synthesis without further purification, because NMR study showed the purity more than 99 %.
1
Yield 2.66 g (50 %); white powder, mp 223-225 °C; H NMR (CDCl3), d 8.36 (2H, d, J = 7.8 Hz, Bipy-
13
3,3’), 7.64 (2H, t, J = 7.8 Hz, Bipy-4,4’), and 7.47 (2H, d, J = 7.8 Hz, Bipy-5,5’); C NMR (CDCl3), d
155.8 (C), 141.8 (C), 139.5 (CH), 128.8 (CH), and 120.3 (CH); IR (KBr) n 3077, 1573, 1543, 1419, 1376,
1154, 1123, 1072, 985, 785, 707, 625, and 479 cm-1.

HETEROCYCLES, Vol. 65, No. 2, 2005
297
Dihydrazinobipyridine (3)9 Dibromobipyridine (2) (0.85 g, 2.7 mmol) was suspended in 16 mL (330
mmol) of hydrazine hydrate under an atmosphere of argon. The mixture was heated to dissolve 2 and
refluxed for 6 h. After cooling to rt, the resulting yellow solid was collected and washed with small
amount of water. The product was used for the next step synthesis without further purification, because
NMR study showed the purity more than 99 %.
Yield 0.56 g (96 %); flaky yellow crystal; mp 205-207 °C; 1H NMR (DMSO-d6), d 7.4-7.6 (4H, m, Bipy-
3,3’ and Bipy-4,4’), 6.69 (2H, dd, J = 7.1, 1.8 Hz, Bipy-5,5’), and 4.16 (6H, br s, NH); 13C NMR (DMSO-
d6), d 161.3 (C) 153.8 (C), 137.6 (CH), 109.6 (CH), and 106.8 (CH); IR (KBr) n 3326, 3256, 3033, 1582,
1450, 1390, 1305, 1271, 1168, 1002, 985, 90, 736, 634, 606, and 467 cm-1.
Diazidobipyridine (4)9 Dihydrazinobipyridine (3) (0.30 g, 1.4 mmol) was suspended in 4 mL of conc.
HCl in ice bath under an atmosphere of argon. To the solution, an aqueous solution of NaNO2 (1.58 g,
22.9 mmol in 20 mL of water) was added slowly via addition funnel. The suspension gradually dissolved
to give a pale yellow clear solution. After the addition was completed, the solution was allowed to warm
to rt and stirred for an additional 6 h. The solution was then basified (pH 10-11) with 10 % NaOH and the
resulting white precipitate was collected and washed with copious amount of water. The product was used
for the next step synthesis without further purification, because NMR study showed the purity more than
99 %.
Yield 0.30 g (90 %); white powder; mp 192-193 °C; 1H NMR (DMSO-d6), d 8.52 (2H, dd, J = 1.8, 7.1 Hz,
13
Bipy-3,3’) and 8.0-8.2 (4H, m, Bipy-4,4’, 5,5’); C NMR (DMSO-d6), d 117.6 (CH), 120.8 (CH), 127.7
(C), 133.1 (CH), and 148.5 (C); IR (KBr) n 3452, 3092, 1632, 1562, 1520, 1497, 1417, 1386, 1365, 1344,
1286, 1249, 1183, 164, 1123, 1096, 1038, 1004, 922, 808, 797, 750, 661, 600, 559, and 513 cm-1.
Diaminobipyridine (5)10 Diazidobipyridine (4) (0.37 g, 1.6 mmol) was added into 10 mL of mixture of
methanol-water (7:3) under an atmosphere of argon. To the suspension, tri-n-butylphosphine (1.0 mL, 4.1
mmol) was added, and the solution was stirred for 5 h at room temperature. The solution was
concentrated to dryness in vacuo. The oily residue was washed with hexane and chromatographed on a
silica gel column with ethyl acetate (Rf 0.4). Recrystallization from ethyl acetate afforded 5 as a yellow
crystal.
1
Yield 0.24 g (83 %); light yellow crystal; mp 182-184 °C; H NMR (acetone-d6), d 7.62 (2H, d, J = 7.3
Hz, Bipy-3,3’), 7.47 (2H, t, J = 8.3 Hz, Bipy-4,4’), 6.53 (2H, d, J = 7.8 Hz, Bipy-5,5’), and 5.39 (4H, s,
NH2); 13C NMR (acetone-d6), d 159.9 (C), 155.7 (C), 138.4 (CH), 110.4 (CH), and 108.9 (CH); IR (KBr)
n 3408, 3298, 3122, 1659, 1615, 1537, 1483, 1452, 1328, and 789 cm-1; Anal. Calcd for C H10N4: C 64.50,
10
H 5.41, N 30.09. Found: C 64.49, H 5.57, N 28.23.

298
HETEROCYCLES, Vol. 65, No. 2, 2005
Diacetate ester (6) Diaminobipyridine (5) (0.42 g, 2.3 mmol) was dissolved in 3 mL of anhydrous
pyridine under an atmosphere of Argon. To the solution, acetoxyacetyl chloride (0.75 mL, 6.8 mmol) was
added slowly in ice bath and then the solution was stirred for 2 h. The solution was diluted with 10 mL of
dichloromethane and washed with water. The organic phase was separated, dried with anhydrous MgSO4,
and concentrated to dryness under reduced pressure. The residue was washed with a small amount of
chloroform to give a white powder. The product was used for the next step synthesis without further
purification, because elemental analysis and NMR study showed the purity more than 99 %.
Yield 0.683 g (79 %); white powder, mp 241-244°C; 1H NMR (DMSO-d6) d 10.70 (2H, s, NH), 8.04 (4H,
d, J = 6.8 Hz, Bipy-3,3', Bipy-5,5'), 7.96 (2H, t, J = 6.8 Hz, Bipy-4.4'), 4.79 (4H, s, CH2), and 2.13 (6H, s,
13
CH3); C NMR (DMSO-d6) d 170.0 (CO), 166.4 (C), 153.3 (C), 150.9 (C), 139.3 (CH), 116.1 (CH),
113.9 (CH), 62.4 (CH2), and 20.3 (CH3); IR n 3283, 1727, 1697, 1590, 1567, 1539, 1431, 1396, 1373,
1360, 1297, 1281, 1244, 1191, 1149, 1071, 794, 754, and 738 cm-1; Anal. Calcd for C18H18N4O6: C 55.96,
H 4.70, N 14.50. Found: C 55.45, H 4.82, N 14.13.
Diol (7) Diacetate ester (6) (0.77 g, 2.0 mmol) was dissolved in 10 mL of methanol. To the solution,
10 % aqueous solution of K2CO3 (10 mL) was added and then the solution was stirred for 2 h at rt. The
white precipitate was collected and washed with copious amount of water. The product was used for the
next step synthesis without further purification, because elemental analysis and NMR study showed the
purity more than 99 %.
1
Yield 0.582 g (97%); white powder; mp 260-262°C; H NMR (DMSO-d6) d 8.10 (2H, d, J = 8.0 Hz,
Bipy-5,5’), 8.03 (2H, d, J = 8.0 Hz, Bipy-3,3’), 7.92 (2H, t, J = 8.0 Hz, Bipy-4,4’), and 4.10 (4H, s, CH2);
13C NMR (DMSO-d6) d 170.8 (CO), 153.2 (C), 150.2 (C), 138.7 (CH), 115.9 (CH), 113.2 (CH), and 61.6
(CH2); IR (ATR) n 3397, 3358, 1666, 1585, 1568, 1529, 1432, 1377, 1326, 1287, 1232, 1203, 1068, 796,
704, and 696 cm-1; Anal. Calcd for C14H14N4O4: C 55.63, H 4.67, N 18.53. Found: C 54.87, H 4.65, N
18.15.
Monotrityl alcohol (8)11 Diol (7) (0.40 g, 1.3 mmol) was added into 2 mL of anhydrous pyridine under
an atmosphere of Argon. To the suspension, 4,4’-dimethoxytrityl chloride (0.88 g, 2.5 mmol) were added
and then the suspension was stirred for 1 h at 60°C. The reaction was quenched by an addition of
methanol (1 mL) and triethylamine (0.7 mL, ca. 5 mmol). The reaction mixture was diluted with 10 mL
of dichloromethane and then washed twice with 5 % aqueous NaOH (100 mL). The organic phase was
dried with anhydrous MgSO4 and concentrated in vacuo. The residue was subjected to silica gel column
chromatography (dichloromethane : diethylamine = 100 : 1) and the fraction of Rf 0.2 was collected. The

HETEROCYCLES, Vol. 65, No. 2, 2005
299
fraction was concentrated to dryness in vacuo and the residue was washed with dichloromethane and
ether to give a pale yellow crystal. Recrystallization from propanol afforded 8 as a pale yellow crystal.
1
Yield 0.45 g (56 %); pale yellow crystal; mp 249-251°C; H NMR (DMSO-d6) d 9.96 (1H, s, NH), 9.75
(1H, s, NH), 8.14 (1H, d, J = 6.8 Hz, Bipy-3), 7.91-8.05 (5H, m, Bipy), 7.48 (2H, d, J = 7.3 Hz, DMTr),
7.36 (2H, t, J = 7.3 Hz, DMTr), 7.34 (4H, d, J = 8.8 Hz, DMTr), 7.28 (1H, t, J = 7.3 Hz, DMTr), 6.93 (4H,
d, J = 8.8 Hz, DMTr), 5.81 (1H, t, J = 5.9 Hz, OH), 4.09 (2H, d, J = 5.9 Hz, CH2), 3.89 (2H, s, CH2), and
13
3.73 (6H, s, OCH3); C NMR (DMSO-d6) d 171.4 (CO), 168.1 (CO), 158.2 (C), 153.4 (C), 153.2 (C),
150.7 (C), 150.5 (C), 144.5 (C), 139.5 (CH), 139.4 (CH), 135.1 (C), 129.7 (CH), 128.0 (CH), 127.6 (CH),
126.9 (CH), 116.1 (CH), 116.0 (CH), 113.8 (CH), 113.5 (CH), 113.3 (CH), 86.5 (C), 63.8 (CH2), 61.6
(CH2), and 55.0 (CH3); IR (ATR) n 3372, 1689, 1608, 1585, 1568, 1512, 1440, 1377, 1341, 1295, 1255,
1178, 1152, 1078, 1035, 993, 829, 803, 771, 727, and 704 cm-1; Anal. Calcd for C35H32N4O6: C 69.52, H
5.33, N 9.27. Found: C 68.72, H 5.60, N 9.12.
Amidite (9)11 Monotrityl alcohol (8) (0.20 g, 0.33 mmol) was suspended in 5 mL of anhydrous
dichloromethane under an atmosphere of Argon. Additional diisopropylethylamine (0.29 mL, 1.69 mmol)
dissolved 8 to give a clear pale yellow solution within 5 min. To the solution, chloro(diisopropylamino)-
(b-cyanoethoxy)phosphine (0.19 mL, 0.83 mmol) was added and the solution was stirred for 2 h. Analysis
by TLC indicated the presence of a new component and disappearance of 8. The reaction mixture was
diluted with 5 mL of dichloromethane, washed twice with 5 % aqueous NaHCO3 (10 mL), dried with
anhydrous MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel
(dichloromethane : ethyl acetate : triethylamine = 100 : 50 : 1). The component of Rf 0.9 was collected
and concentrated to dryness in vacuo. The residual white powder was dissolved in 3 mL of
dichloromethane and poured into a cold hexane at -70°C to precipitate the desired product (9) as a
colorless powder.
1
Yield 0.146 g (55 %); white powder; mp 132-134°C, H NMR (CDCl3), d 9.08 (1H, s, NH), 9.05 (1H, s,
NH), 8.27 (1H, d, J = 8.3 Hz, Bipy), 8.17 (1H, d, J = 7.3 Hz, Bipy), 8.15 (1H, d, J = 8.3 Hz, Bipy), 8.08
(1H, d, J = 7.3 Hz, Bipy), 7.88 (1H, t, J = 8.3 Hz, Bipy), 7.81 (1H, t, J = 8.3 Hz, Bipy), 7.49 (2H, d, J =
7.3 Hz, DMTr), 7.25-7.39 (7H, m, DMTr), 6.87 (4H, d, J = 8.8 Hz, DMTr), 4.27-4.39 (2H, m, POCH2),
3.90-3.99 (4H, m, COCH2), 3.73-3.83 (8H, m, OCH3, NCH), 2.70 (2H, dt, J = 1.9, 6.4 Hz, CH2CN), and
1.29 (12H, dd, J = 6.8, 14.2 Hz, CH3); 13C NMR (CDCl3) d 168.6 (CO), 158.9 (C), 153.8 (C), 153.7 (C),
150.0 (C), 143.8 (C), 139.3 (CH), 139.2 (CH), 134.8 (C), 130.0 (CH), 128.2 (CH), 128.0 (CH), 127.3
(CH), 117.3 (CN), 117.1 (CH), 116.9 (CH), 114.1 (CH), 114.2 (CH), 113.5 (CH), 88.0 (C), 64.1 (CH2),
2
2
63.5 (d, JCP = 17.0 Hz, CH2), 58.8 (d, 2JCP = 13.9 Hz, CH2), 55.3 (OCH3), 43.6 (d, JCP = 12.2 Hz, CH),

300
HETEROCYCLES, Vol. 65, No. 2, 2005
24.7 (m, CH3), and 20.5 (d, 3JCP = 7.3 Hz, CH2); 31P NMR (CDCl3) d 151.45; IR (KBr) n 3392, 2969, 2933,
1699, 1609, 1585, 1570 1518, 1440, 1377, 1297, 1253, 1179, 1078, 1039, 981, 829, and 801 cm-1; Anal.
Calcd for C44H49N6O7P: C 65.66, H 6.14, N 10.44. Found: C 64.29, H 5.92, N 10.20.
ACKNOWLEDGEMENTS
The authors thank Dr. Y. Umebayashi (Kyushu University) for useful discussion on the conformation and
the reactivity of the intermediates from the viewpoint of computational chemistry. This work was
partially supported by Kyoritsu Chemical & Co., Ltd. (to M.T.), the Venture Business Laboratory of
Kumamoto University, and a Grant-in-Aid for Scientific Research (No. 15350047) from the MEXT
(Ministry of Education, Culture, Sports, Science, and Technology of Japan) (to T.I.).
REFERENCES
1. G. T. Harmanson, ‘Bioconjugate Techniques’, Academic Press, New York, 1996.
2. for example S. Tyagi, Nat. Biotechnol., 1996, 14, 303; P. Zhang, T. Beck, and W, Tan, Angew.
Chem., Int. Ed., 2001, 40, 402; B. Dubertret, M. Calame, and A. J. Libchaber, Nat. Biotechnol., 2001,
19, 365; H. K. Kuhn, V. V. Demidov, J. M. Coull, M. J. Fiandaca, B. D. Gildea, and M. D. Frank-
Kamenetskii, J. Am. Chem. Soc., 2002, 124, 1097; T. Ihara, S. Tanaka, Y. Chikaura, and A. Jyo,
Nucleic Acids Res., 2004, 32, e105; T. Ihara, T. Fujii, M. Mukae, Y. Kitamura, and A. Jyo, J. Am.
Chem. Soc., 2004, 126, 8880.
3. for example ‘Nanobiotechnology’ (Part III DNA-based Nanostructures), ed. by C. M. Niemeyer
and C. A. Mirkin, Wiley-VCH, Weinheim, 2004, pp. 227-342, and refs therein.
4. G. M. Emilsson and R. R. Breaker, Cell. Mol. Life Sci., 2002, 59, 596; A. Jäschke, Curr. Opin.
Struct. Biol., 2001, 11, 321.
5. M. Rimmele, ChemBioChem, 2003, 4, 963.
6. J. Kurreck, Eur. J. Biochem., 2003, 270, 1628.
7. K. Araki, T. Kuboki, M. Yamada, and S. Shiraishi, J. Chem. Soc., Chem. Commun., 1992, 1060; J. P.
Schneider and J. W. Kelly, J. Am. Chem. Soc., 1995, 117, 2533.
8. J. E. Parks, B. E. Wagner, and R. H. Holm, J. Organomet. Chem., 1973, 56, 53; T. Garber and D. P.
Rillema, Syn. Commun., 1990, 20, 1233.
9. J. P. Schneider, R. S. Topgi, and J. W. Kelly, Syn. Commun., 1992, 22, 1033.
10. L. Horner and A. Gross, Liebig Ann. Chem., 1955, 591, 117; W. S. Mungall, G. L. Greene, G. A.
Heavner, and R. L. Letsinger, J. Org. Chem., 1975, 40, 1659; M. Vaultier, N. Knouzi, and R. Carrie,
Tetrahedron Lett., 1983, 24, 763; H. Suzuki and K. Takaoka, Chem. Lett., 1984, 1733.

HETEROCYCLES, Vol. 65, No. 2, 2005
301
11. Y. Saito, A. Nyilas, and L. A. Agrofoglio, Carbohydr. Res., 2001, 331, 83; L. M. Easterwood, E. A.
Veliz, and P. A. Beal, J. Am. Chem. Soc., 2000, 122, 11537; A. K. Ogawa, Y. Wu, D. L. McMinn, J.
Liu, P. G. Schultz, and F. E. Romesberg, J. Am. Chem. Soc., 2000, 122, 3274; D. J. Hurley, S. E.
Seaman, J. C. Mazura, and Y. Tor, Org. Lett., 2002, 4, 2305; H. Molrales-Rojas and E. T. Kool, Org.
Lett., 2002, 4, 4377; R. L. Letsinger and T. Wu, J. Am. Chem. Soc., 1995, 117, 7323.
12. S. T. Howard, J. Am. Chem. Soc., 1996, 118, 10269.