Synthesis of a β-glycoside functionalized GΛC motif for self-assembly into rosette nanotubes with predefined length

Article abstract of DOI:10.1016/j.tetlet.2010.11.122

Progress toward the synthesis of guanine-cytosine (GΛC) oligonucleotides for the spontaneous self-assembly of rosette nanotubes (RNTs) with predefined length is described. Highlighted is the synthesis of the β-glycoside functionalized GΛC base along with a new nitrogen protecting group strategy that is compatible with Boc and Bn groups.

Full text of DOI:10.1016/j.tetlet.2010.11.122

Tetrahedron Letters 52 (2011) 661–664
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a b-glycoside functionalized G
rosette nanotubes with predefined length
KC motif for self-assembly into
⇑
Rachel L. Beingessner, Julian A. Diaz, Usha D. Hemraz, Hicham Fenniri
National Institute for Nanotechnology and Department of Chemistry, University of Alberta, 11421 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2M9
a r t i c l e i n f o
a b s t r a c t
Article history:
Progress toward the synthesis of guanine–cytosine (GKC) oligonucleotides for the spontaneous self-
Received 19 September 2010
Revised 22 November 2010
Accepted 23 November 2010
Available online 27 November 2010
assembly of rosette nanotubes (RNTs) with predefined length is described. Highlighted is the synthesis
of the b-glycoside functionalized G C base along with a new nitrogen protecting group strategy that
is compatible with Boc and Bn groups.
K
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Keywords:
Rosette nanotubes
Nucleosides
Glycosylation
Protecting group
1. Introduction
2. Results and discussion
G
K
C base 1 (Fig. 1) is a self-complementary guanine–cytosine
The studies commenced by investigating the protecting group
strategies that would allow us to readily access the free amide 5
for the ensuing glycosylation reaction. We initially attempted a
hybrid molecule that was shown to self-assemble1,2 in aqueous
or organic solvents into six-membered supermacrocycles main-
tained by 18-hydrogen bonds. These assemblies further organize
into linear stacks (termed rosette nanotubes, RNTs) with a central
channel running the length of the stack. In principle, any functional
selectivede-allylation reaction of an N-allylated GKC base precursor
4 (PG = Allyl), the synthesis of which we have reported previously.1
Despite using many different conditions, standard protocols such as
group R covalently linked to the G
K
C base 1 ends up being ex-
Rh-catalyzed isomerization6 and Pd-catalyzed
p
-allyl methodolo-
gies7 were unproductive in this deprotection reaction.
An alternative protecting group, trimethysilylethane
pressed on the outer surface of the RNTs, thereby providing a
‘built-in’ strategy to alter the RNTs’ chemical and physical proper-
ties and ultimately their applications.
(TMSCH2CH2–) was next explored since its removal is known to
be carried out under mild conditions (fluoride induced fragmenta-
tion).8 Furthermore, initial attempts at the SNAr reaction between
2,4,6-trichloropyrimidine-5-carbaldehyde (2) and TMS-ethylamine
proceeded in good yield (Scheme 2). Overall, compound 12 was
synthesized from pyrimidine 2 in nine-steps in 82% average step-
wise yield (18% overall). Unfortunately, treatment of 12 with fluo-
ride sources such as TBAF, Et3NÁ3HF, C6H5NÁHF, CsF and KF under a
variety of reaction conditions failed to unmask the amide. Basic
(e.g., nBuLi) and acidic deprotection conditions (e.g., 4 N HCl in
dioxane at 45 °C, 4 h) were also unsuccessful. The latter acidic con-
ditions did remove the Bn and the Boc groups however, to provide
While we have reported several strategies to functionalize the
GK
C motif,1a–d they either relied on early functionalization via
SNAr, reductive amination or on Suzuki cross-coupling late in the
synthetic scheme. Herein our aim was to develop a strategy that
would allow us to streamline the synthesis of RNTs with prede-
fined length by taking advantage of the automated DNA synthesis
methodology. A convergent approach illustrated in Scheme 1 was
proposed, whereby the free amide nitrogen atom of intermediate
5 would be directly alkylated with the desired electrophile3 to pro-
vide 6. Conversion to the corresponding phosphoramidite 74 fol-
lowed by oligomerization using automated DNA synthesis,5 then
global deprotection, would furnish the corresponding G
K
C oligo-
GK
C base 13 in 80% yield (Scheme 2).
mers. The latter are anticipated to undergo spontaneous self-
assembly in water to generate discrete tubular architectures whose
length is pre-determined by the length of the GKC base oligomer.
Given the unusual stability of the silyl derivative 12, we decided
to develop a fragmentation strategy that would yield the desired
compound according to Scheme 3. We reasoned that the fragmen-
tation could be triggered thermally via the cyclic transition state
22 (Path 1), or promoted with a primary or secondary amine (Path
2). In the latter case, imine 17 obtained from aldehyde 16 could
⇑
Corresponding author.
E-mail address: hicham.fenniri@ualberta.ca (H. Fenniri).
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.122

662
R. L. Beingessner et al. / Tetrahedron Letters 52 (2011) 661–664
D
N(Boc)2
N
BnO
N
N(Boc)2
N
BnO
N
A
R2NH2
H2O
H
H
N
O
N
N
D
A
H
BocN
N
BocN
N
N
O
D
N
N
O
A
R2
H
16
17
N
N
N
R
O
O
‡
H2O
Path 2
Path 1
1
Figure 1. GKC motif. ‘D’ and ‘A’ refer to hydrogen bond donors and acceptors,
N(Boc)2
N
BnO
N
respectively.
N(Boc)2
N
BnO
N
BocN
N
N
O
H
BocN
N
N
O
H
O
N
O
N
O
22
19
H
Cl
NHPG
Cl
N
Cl
steps
(a)
H
NH2PG
(a)
N
O
N
R2
Cl
Cl
2
R4O
3
N(Boc)2
N
BnO
N
O
X
+
H2O
OR1 NR3
N
OR1 NR3
N
N
O
20
R2
R5O
(b)
N
–PG
(a)
N
BocN
N
N
OH
21
5
R2N
N
N
H
O
R2N
N
N
O
R2
4
5
PG
N
N
R2
OR1
N
N
N
OR1
NR3
DMTO
NR3
N
O
N
N
N
R4O
Scheme 3. Proposed mechanism for the deprotection of 16.
O
N
(c)
NC
O
N
O
O
P
R5O
6
7
O
OBn
N
N(Boc)2
N
BnO
N
N
G C
HO
O
(g-i)
(a-f)
BocN
N
2
BocN
NH
N
N
O
O
P
14
15
Global
deprotection
O
O-
G C
Rosette
Nanotubes
O
O
(d)
N(Boc)2
N
NR1R2
N
BnO
N
BnO
N
n
R2NH2
rt
(j,k)
BocN
OH
8
BocN
N
N
O
N
N
O
H
Scheme 1. Reagents and conditions: (a) according to the synthetic strategy detailed
16
5, R1 = R2 = Boc
18, R1 = H, R2 = CH2Ph
in this paper; (b) the ribose moiety would be prepared and coupled to the GKC base
according to previously reported procedures;3 (c) according to reported proce-
dures;4 (d) automated DNA synthesis.5
O
Scheme 4. Reagents and conditions: (a) but-3-en-1-amine, CH2Cl2, quant.; (b)
MeNH2, 4 h, 92%; (c) BnOH, NaH, THF, 74%; (d) (Boc)2O, DMAP, Et3N, THF, 98%; (e)
NH2OHÁHCl, KHCO3, MeOH, 53%; (f) TFAA, Et3N, THF, 70%; (g) N-(chlorocarbonyl)
isocyanate, Et3N, CH2Cl2; (h) 7 N NH3 in MeOH, 95%, two-steps; (i) (Boc)2O, DMAP,
Et3N, THF, 62%; (j) OsO4, NMO, acetone/H2O, 77%; (k) NaIO4, CH2Cl2/H2O, 89%.
N
H
N
O
N
H
H
BnO
N
Cl
N
(a)
(b-f)
TMS
TMS
2
N
N
tautomerize to the corresponding intermediate enamine 19, which
can then eliminate imine 20 to furnish the target compound 5 (tau-
tomer of 21). To test this strategy compound 16 was synthesized in
12-steps according to Scheme 4 and then treated with a variety of
amines (Table 1).
While the thermal fragmentation gave several unidentified by-
products along with target compound 5, activation with primary
amines gave 5 in good yields as shown in Table 1. Secondary
amines such as diethylamine were unproductive and only starting
material was recovered after 24 h. Aromatic amines such as aniline
were also ineffective, giving a mixture of products. Interestingly,
performing the reaction for longer periods of time (>36 h) or heat-
ing (>40 °C) with 0.25–2.0 equiv of benzylamine led to a decline in
the yield caused by the formation of the substituted product 18
(Scheme 4).
10
11
BocN
Cl
O
N
NH2
N
BnO
N
N(Boc)2
N
(g-i)
(j)
HN
HN
N
O
BocN
N
N
O
12
13
TMS
TMS
Scheme 2. Reagents and conditions: (a) trimethylsilylethylamine hydrochloride,9
DIPEA, CH2Cl2, 60%; (b) MeNH2, THF, 88%; (c) BnOH, NaH, THF, 77%; (d) (Boc)2O,
DMAP, Et3N, THF, 94%; (e) NH2OHÁHCl, pyridine; (f) TFAA, Et3N, THF, 79%, two-
steps; (g) N-(chlorocarbonyl) isocyanate, CH2Cl2, 78%; (h) 7 N NH3 in MeOH, 97%; (i)
(Boc)2O, DMAP, Et3N, THF, 79%; (j) 4 N HCl in dioxane, 80%.

R. L. Beingessner et al. / Tetrahedron Letters 52 (2011) xxx–xxx
663
Table 1
such as Bz, that are more traditionally used for the automated
DNA synthesis technology.
Deprotection of 16 in the presence of primary amines (in 1,2-dichloroethane, at room
temperature for 24 h)
Entry
1
Amine
-Lysine
Yield (%)
56
4. Experimental
L
2
3
4
Methylamine
n-Butylamine
Benzylamine
64
67
92
Generally, unless otherwise noted, all of the reactions were per-
formed under an atmosphere of N2 using an oven dried glassware
equipped with a magnetic stir bar and a rubber septum. Methanol
and dichloromethane were dried using the solvent purification sys-
tem. All commercial reagents were used without purification un-
less otherwise stated. Reactions were monitored by TLC analysis
using UV254 pre-coated TLC plates and visualized under UV light.
1H and 13C NMR spectra were in the specified deuterated solvents.
The NMR data are presented as follows: chemical shift, assignment,
peak multiplicity, coupling constant, integration. The following
abbreviations were used to explain the multiplicities: s = singlet,
d = doublet, br s = broad singlet and m = multiplet.
N(Boc)2
BnO
N
N(Boc)2
N
BnO
N
N
BocN
N
N
O
BocN
TolO
N
N
O
H
5
NaH, THF
rt
+
O
TolO
23
O
24
OTol
dr β:α = 94:6
4.1. tert-Butyl 4-(benzyloxy)-7-oxo-7,8-dihydropyrimido[4,5-
d]pyrimidine-2,5-diyltricarbamate (5)
Cl
OTol
NH2
N
BnO
N
Benzylamine (7
l
L, 6 Â 10À2 mmol) was added to a solution of
H
H
TolO
aldehyde 16 (20 mg, 3.1 Â 10À2 mmol) in 1,2-dichloroethane
(1.0 mL) at room temperature. After stirring for 24 h, the reaction
was quenched with H2O and the product was extracted with
CH2Cl2 (3Â). The combined organic layers were dried over Na2SO4,
filtered and concentrated in vacuo. Purification by flash chroma-
tography on silica gel (20% EtOAc in hexanes) afforded 17 mg of
compound 5 (C29H38N6O8, 92%) as a white foam. Rf = 0.65 (70%
EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 7.41–7.32 (C13H–
H
O
HN
N
N
O
TolO
H
SiO2, 90°C
15 h
+
H
O
N
N
H
NH
TolO
O
N
N
OBn
H
H
25 (β), 22%
TolO
NH2
26 (α), 10%
C
17H, m, 5H), 5.54 (C11H, s, 2H), 3.41 (C10H, s, 3H), 1.55 (C20H, s,
9H), 1.30 (C24H, C27H, s, 18H); 13C NMR (100 MHz, CDCl3) 164.8
(C4), 161.8, 161.4, 161.0, 156.6, 152.4 (C1, C2, C5, C21, C18), 148.6
(C22, C25), 134.5 (C12), 128.4, 128.3, 128.2 (C13–C17), 92.6 (C3),
83.6 (C19), 83.0 (C23, C26), 69.9 (C11), 34.8 (C10), 28.0 (C20), 27.7
(C27, C24); ESI-HRMS: calcd for [M+H+]/z, 599.2829; observed,
599.2824.
Scheme 5. Glycosylation and deprotection reaction of 5.
Finally, with compound 5 in hand, we proceeded to test the gly-
cosylation reaction. As shown in Scheme 5, reaction of 5 with the
toluyl-protected deoxyribose 233 was successfully performed in
THF using NaH as a base.10 The resulting alkylated G
KC motif 24
was very unstable, however, at both room temperature and
À20 °C due to the elimination of the sugar moiety, which led to fur-
ther decomposition. In order to improve its stability, the Boc
groups of 24 were removed by adsorbing over silica gel under high
vacuum. Subsequent purification using silica gel chromatography
and reverse phase HPLC afforded the desired b-anomer 25 in 22%
4.2. (2R,3S,5R)-5-(4-Amino-5-(benzyloxy)-7-(methylamino)-2-
oxopyrimido[4,5-d]pyrimidin-1(2H)-yl)-2-((4-methylphenyl
carbonyloxy)methyl) tetrahydrofuran-3-yl 4-methylbenzoate
(25)
Compound 5 (40 mg, 0.067 mmol) was dissolved in dry THF
(1 mL) and then treated with NaH (5 mg, 60% dispersion in oil,
0.13 mmol). After sonicating until dissolution, the mixture was
stirred for an additional 5 min before 233 (26 mg, 0.067 mmol)
was added. Upon stirring for 1 h, the reaction was quenched with
water (five drops) and concentrated (rotovap). Purification by silica
gel flash chromatography (EtOAc/hexanes followed by CH3OH/
EtOAc/hexanes) afforded 60 mg of 24 in 94% yield. Rf = 0.3
(25:5:70 EtOAc/CH2Cl2/hexanes). This material was then dissolved
in CH2Cl2, treated with SiO2 (200 mg) and rotovaped to dryness.
The adsorbed compound 24 was then placed under high vacuum
and heated to 90 °C. After 15 h, the product was dry loaded onto
a silica column and eluted with a gradient of hexanes/CH2Cl2 fol-
yield (two-steps). The corresponding
lated in 10% yield (dr b/ , 96/4). Structural elucidation of both
the b and -adducts were unambiguously established using 1D
a-anomer 26 was also iso-
a
a
and 2D NMR techniques (ROESY, COSY, HSQC, HMBC). In both
cases, the presence of two conformational states11 was evident in
the 1H NMR taken at 25 °C in DMSO-d6.
3. Conclusion
In this paper, we have described the synthesis of the b-glycoside
compound 25. This is an important key step for the synthesis of
GKC oligonucleotides, which we anticipate will readily self-assem-
ble into RNTs with predefined length. During the course of these
studies, we have also optimized a protecting group strategy for
lowed by EtOAc/MeOH to provide a mixture of b and a-anomers
25 and 26, respectively. Separation by HPLC on a reverse phase
semi-preparative column (79:21 MeOH/H2O, flow rate 5 mL/min)
afforded 9 mg of the pure b-anomer 25 (retention time 6.47 min)
in 22% yield. Rf = 0.22 (2% MeOH in CH2Cl2). 1H NMR (600 MHz,
DMSO-d6) d (ppm) 7.94–7.50 (C27H–C28H, C30H–C31H, C36H–C37H,
the urea nitrogen12 of the G
KC base. More specifically, it was
determined that oxidative cleavage of alkene 15 followed by the
treatment of aldehyde 16 with a primary amine (benzylamine) at
room temperature in 1,2-dichloroethane for 24 h, generated the
corresponding deprotected 5 in good yield. Current efforts will be
focused on the synthesis of the phosphoramidite 7 from 25 as well
as exploring alternative protecting group strategies for R2 and R3
C40H–C41H, 8H), 7.40–7.32 (C12H–C16H, m, 5H), 7.34–7.09 (C21Ha,
NH, m, 4H), 5.86–5.81 (C23Hd, ddt, J = 15.3, 8.2, 5.9 Hz, 1H), 5.62
(C10H, s, 1H), 5.54 (C10H, s, 1H), 4.63–4.59 (C33H, dt, J = 11.7,

664
R. L. Beingessner et al. / Tetrahedron Letters 52 (2011) 661–664
5.3 Hz, 1H), 4.53–4.50 (C24He, dd, J = 11.2, 7.0 Hz, 0.5H), 4.48–4.45
(C24He, dd, J = 11.2, 7.0 Hz, 0.5H), 4.43–4.40 (C33H, dd, J = 11.7,
5.3 Hz, 0.5H), 4.38–4.35 (C33H, dd, J = 11.7, 5.3 Hz, 0.5H), 3.18–
3.15 (C22Hb, m, 0.5H), 3.12–3.00 (C22Hb, m, 0.5H), 2.88–2.86 (C9H,
m, 3H), 2.45–2.40 (C22Hc, m, 0.5H), 2.38, 2.34 (C32H, C39H, s, 6H),
2.34–2.29 (C22Hc, m, 0.5H); 13C NMR (150 MHz, DMSO-d6) 166.6,
166.1, 165.5, 165.4, 161.0, 160.7, 160.7 (C1, C2, C5, C4, C34, C25),
153.9 (C20), 143.6, 136.3, 136.0 (C11, C29, C38), 129.32, 129.29,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.122.
References and notes
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129.22, 129.12, 128.5, 128.43, 128.41, 128.2, 128.1, 126.7 (C12
–
C16, C26–C28, C30–C31, C35–C37, C40–C41), 82.2 (C3), 82.1, 82.0 (C21),
81.1, 81.0 (C24), 75.8, 75.6 (C23), 68.2, 67.9 (C10), 65.2 (C33), 35.5,
35.1 (C22), 27.8 (C9), 21.2, 21.1 (C32, C39); ESI-HRMS: calcd for
[M+H+]/z, 651.2562; observed, 651.2558; calcd for [M+Na+]/z,
673.2381; observed, 673.2377.
4.3. (2R,3S,5S)-5-(4-Amino-5-(benzyloxy)-7-(methylamino)-2-
oxopyrimido[4,5-d]pyrimidin-1(2H)-yl)-2-((4-methylphenyl
carbonyloxy)methyl)tetra hydrofuran-3-yl 4-methylbenzoate
(26)
Four milligram of the
a-anomer 26 (retention time 5.66 min)
was also obtained in 10% yield. Rf = 0.20 (2% MeOH in CH2Cl2)
1H NMR (600 MHz, DMSO-d6) d (ppm) 7.91–7.50 (C27H–C28H,
C
C
30H–C31H, C36H–C37H, C41H–C42H, m, 8H), 7.39–7.32 (C12H–
16H, m, 5H), 7.28–7.21, 7.14–7.13 (NH, m, 3H), 7.16–7.14,
(C21Ha, m, 0.5H), 7.05–7.02 (C21Ha, m, 0.5H), 5.64–5.59 (C10H, m,
1H), 5.55–5.52 (C10H, m, 1H), 5.50–5.48 (C23Hd, m, 0.5H), 5.45–
5.41 (C23Hd, m, 0.5H), 5.06–5.01 (C24He, m, 0.5H), 4.99–4.94
(C24He, m, 0.5H), 4.50–4.49 (C33H, m, 1H), 4.42–4.36 (C33H, m,
1H), 3.19–3.16 (C22Hc, m, 0.5H), 2.92–2.89 (C22Hc, m, 0.5H), 2.86–
2.84 (C9H, m, 3H), 2.76–2.69 (C22Hb, m, 1H), 2.38–2.35 (C32H,
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C
39H, m, 6H); 13C NMR (600 MHz, DMSO-d6) d (ppm) 167.1,
166.4, 166.0, 161.6, 161.4, 161.0 (C1, C2, C5, C4, C34, C25), 154.8
(C20), 144.4, 144.3, 136.8, 136.5 (C11, C29, C38), 129.9, 129.8,
129.73, 129.72, 129.67, 129.64, 128.94, 128.92, 128.87, 128.7,
128.6, 127.11, 127.05 (C12–C16, C26–C28, C30–C31, C35–C37, C40
–
9. Fialova, V.; Bazant, V.; Chvalovsky, V. Collect. Czech. Chem. Commun. 1973, 38,
3837. A higher yield of the product was obtained when the reaction was carried
out with 1.2 equiv of LAH.
C41), 82.6 (C3, C21), 79.5 (C24), 74.7 (C23), 68.6, 68.3 (C10), 65.2
(C33), 34.0, 33.6 (C22), 28.4 (C9) 21.7, 21.6 (C32, C39); ESI-HRMS:
calcd for [M+H+]/z, 651.2562; observed, 651.2559; calcd for
[M+Na+]/z 673.2381; observed, 673.2378.
10. Wang, R.-W.; Gold, B. Org. Lett. 2009, 11, 2465.
11. (a) Saenger, W. Angew. Chem., Int. Ed. Engl. 1973, 12, 591; (b) Sundaralingam, M.
Ann. N. Y. Acad. Sci. 1975, 255, 3; (c) Altona, C.; Sundaralingam, M. J. Am. Chem.
Soc. 1972, 94, 8205; (d) Plavec, J.; Tong, W.; Chattopadhyaya, J. J. Am. Chem. Soc.
1993, 115, 9734.
12. (a) For examples of amide and urea protecting groups see: ref.8; (b) Reddy, D.
R.; Iqbal, M. A.; Hudkins, R. L.; Messina-McLaughlin, P. A.; Mallamo, J. P.
Tetrahedron Lett. 2002, 43, 8063; (c) Knapp, S.; Hale, J. J.; Bastos, M.; Gibson, F.
S. Tetrahedron Lett. 1990, 31, 2109; (d) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J.
Org. Chem. 1983, 48, 2424; (e) Hungate, R. W.; Chen, J. L.; Starbuck, K. E.;
Macaluso, S. A.; Rubino, R. S. Tetrahedron Lett. 1996, 37, 4113.
Acknowledgments
We thank Dr. Jesus G. Moralez, Dr. Mathivanan Packiarajan, and
Dr. Azizul Haque for the preliminary work on this project. We
thank the Natural Science and Engineering Research Council of
Canada, Canada National Research Council, and the University of
Alberta for supporting this project.