Computation-guided improved one-pot synthesis of macrocyclic cation-binding aromatic pyridone pentamers

Article abstract of DOI:10.1039/c6ob01841f

By using polar DMF to relax the H-bonded rigid backbone and to lower the energetic penalty associated with the sterically-crowded environment, the yields for BOP-mediated one-pot synthesis of pentameric macrocycles can be improved from 10-25% as obtained

Full text of DOI:10.1039/c6ob01841f

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Biomolecular Chemistry
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Computation-guided improved one-pot synthesis
of macrocyclic cation-binding aromatic pyridone
pentamers†
Cite this: DOI: 10.1039/c6ob01841f
Received 23rd August 2016,
Accepted 8th September 2016
a
b
c
DOI: 10.1039/c6ob01841f
Vicky Ziman Zeng, Haibin Su and Tianhu Li*
www.rsc.org/obc
By using polar DMF to relax the H-bonded rigid backbone and to 1–6, which comprise five alkylated pyridone motifs that
lower the energetic penalty associated with the sterically-crowded enclose a cooperative cation-binding cavity of 2.85 Å in radius
environment, the yields for BOP-mediated one-pot synthesis of as measured from the center of oxygen nucleus to the cavity
2
e
pentameric macrocycles can be improved from 10–25% as center (Fig. 1). These highly rigidified pentamers exhibit not
8
−1
2h
obtained in CH
2 2 2 2
Cl to 13–47% when 15% DMF in CH Cl was used only tight binding of ∼10 M toward alkali metal cations
+
as the reaction medium.
but also highly selective recognition of Cs ions in the pres-
2
f
ence of 23 other metal ions. Even more interestingly, while
pentamer 1 in the solid state is able to retain both high
binding selectivity and capacity in recognizing ions such as
Cs , Rb and Ba , closely resembling the characteristics of the
binding profile exhibited by this type of pentamer in solution,
ions of various types remain poorly extractable by both 2 and 3
1
a
Since the first report by Gong in 2004, intramolecular
H-bonds of various types have attracted good attention in their
application to conformationally constrain macrocyclic back-
bones containing a non-collapsed cavity for both structural
and functional evolution.
this unique class of H-bonded macrocycles that have been
+
+
2+
1
b,c
Interesting functions arising from
8
in the solid state.
2
a
demonstrated include G-quadruplex stabilization, ion trans-
A relatively efficient BOP-mediated one-pot synthesis proto-
col has been elaborated by the same group, producing penta-
mers carrying different side chains in yields of 10–25% in
2
b
2c–i
3a,b
port and recognition,
guest encapsulation,
reaction
3
c,d
3e
3f
promotion
ling,
and catalysis, molecular sensing, solvent gel-
3
g,h
4
and formation of defined nanostructures.
7c
about a day (Fig. 1). Apparently, this protocol is much
Concurrent with the above advances in structure and func-
tion of H-bonded macrocycles, H-bonding-assisted one-pot
synthesis has also been actively pursued, allowing for the
rapid and efficient production of a number of these H-bonded
macrocycles from their corresponding simple repeating
1
b,c
1a,5
3a
3b
6
units
as reported by Gong,
Huc, Li, Jiang and
2
i,7
Zeng.
These one-pot macrocyclization protocols have greatly
facilitated and, together with those emerging, undoubtedly
will continue to further the functional investigation of
H-bonded macrocycles.
In particular, Zeng and his co-workers recently described
an interesting new class of H-bonded macrocyclic pentamers
a
Singapore American School, 40 Woodlands Street 41, 738547 Singapore
b
Division of Materials Science, 50 Nanyang Avenue, Nanyang Technological
University, 639798, Singapore
Fig. 1 Comparisons of reaction conditions and synthetic efficiency
between Zeng’s macrocyclization conditions and those of our current
c
7c
Division of Chemistry and Biological Chemistry, 21 Nanyang Link, Nanyang
Technological University, 637371 Singapore. E-mail: thli@ntu.edu.sg;
work. A more efficient synthesis of 1–6 was achieved in our work largely
via the use of polar DMF to relax the H-bonded rigid backbone during
the one-pot macrocyclization process. BOP = benzotriazole-1-yl-oxy-
tris-(dimethylamino)-phosphonium hexafluorophosphate; DIEA = diiso-
propyl ethylamine.
Tel: (+) 65-6513-7364
1
†Electronic supplementary information (ESI) available: H NMR and HRMS for
1–6, computational optimized structures with relative energies. See DOI:
10.1039/c6ob01841f
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greener than the stepwise lengthy synthesis process, producing
2
e
2
and 3 in 1–2% yields after months of efforts.
We became interested in this type of pentamer as we envi-
sioned that suitable modifications of the side chains around
the pentameric exterior might lead to a new class of pentagon-
shaped molecules capable of interacting with pentameric pro-
9
2a
teins or even G-quadruplex structures. Therefore, it would
be more desirable if one-pot synthesis of these pentamers can
be further improved. While looking into the ways of improving
the synthesis, we were intrigued to find out how BOP, a steri-
cally bulky coupling reagent, could interact with the key un-
cyclized intermediate, i.e., the H-bonding-rigidified near-
planar pentamer 7 (Fig. 2c), to produce pentamers 1–6.
Fig. 3 Structures of two 7–BOP conjugates type I, 7A and 7B, produced
from the reaction between 7 and BOP. Four and eight alternative confor-
According to the mechanism of BOP-mediated coupling of mations can be generated for 7A and 7B for computational evaluation,
respectively. The dihedral angle of C–OP–O and the corresponding
atoms are shown in purple.
an acid with an amine to produce an amide bond (Scheme 1)
proposed by Castro, the first reactive intermediate I seems to
1
0
experience the largest steric hindrance and should incur the
largest energetic penalty compared to other steps. We therefore
decided to focus on evaluating the energetics of two type I
intermediates, e.g., 7A and 7B that differ from each other
mainly by the relative orientation of the end carboxylate group
(
Fig. 3), using a computational approach.
For both 7A and 7B, four dihedral angles of C–OP–O (e.g.,
45, 135, −45 and −135°, see purple atoms in Fig. 3) were used
to define four starting conformations. For each of these four
dihedral angles, the NvN bond in the triazole group of BOP
can lie at either the left or the right side of the O–N single
bond, leading to a total of eight possible conformations. In 7A,
the placement of the BOP motif toward the interior results in
significant steric hindrance that limits the rotational freedom
of the triazole moiety. As such, only four alternative confor-
Fig. 2 (a) Structure of BOP. (b) and (c) describe the structure of a sim-
plified pentameric intermediate 7 (R = methyl) and its computationally
optimized structure at the level of B3LYP/6-31G(d,p) in the gas phase. A
near-planar geometry leaving no space for BOP can be clearly seen in 7.
mations 7A
group is freely rotatable and a total of eight conformations
B –7B could be generated for analysis and comparison.
1 4
–7A could be generated. For 7B, the triazole
7
1
8
After subjecting these 12 initial structures to computational
optimization and energy calculation at the levels of B3LYP/
-31G(d,p) and B3LYP/6-311+G(2d,p) in the gas phase, respec-
tively, we surprisingly found that, except for 7A that remains
6
4
as a type I structure, the other 11 structures actually were
changed into the structures of types II or V. Table 1 tabulates
these changes and the corresponding relative energies normal-
2
ized based on the most stable conformation 7A with their
corresponding structures compiled in Fig. S1 and S2.†
We have further compared the energy of the near-planar
pentameric backbone in 7 (Fig. 2c) with its correspondingly
distorted backbones in various 7–BOP conjugates, i.e. type I, II
and V intermediates after reaction with BOP. The relative ener-
gies normalized based on near-planar 7 were also included in
Table 1 with their corresponding structures compiled in
Fig. S3 and S4.†
2
Not surprisingly, type II intermediate 7A with the loss of
Scheme 1 Mechanism of BOP-mediated coupling to produce an amide
bond from acid and amine groups via intermediates I–IV as proposed by
Castro. Based on our current computational findings (Table 1), the
the bulky hexamethylphosphoramide group not only is the
most stable among the 12 structures, but also contains the
least distorted pentameric backbone that is less stable than
1
0
reaction might also go through intermediate V, which was not proposed
previously but more stable than I by 11.7 kcal mol−
1
.
planar 7 by only 5.2 kcal mol . For comparison, the same
−1
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Table 1 Structural changes after computation and relative energies in ity of the H-bonded backbone by using polar molecules such
a
7
–BOP conjugates and in 7
as DMF or DMSO, which are able to strongly compete with
H-bond donors and acceptors in the formation of H-bonds.
Zeng’s early investigations, however, demonstrated that the
yields of the BOP-mediated one-pot synthesis of 1 decrease
from 25% to 8, 11 and 6% when 100% DMF, 50% DMF in
Relative energy
(kcal mol−
1
Structure after
computation
(7–BOP)
)
Dihedral angle
(C–OP–O, °)
b
c
Isomer
7–BOP
7
2 2
CH Cl and 100% DMSO were used as the reaction medium,
7
7
7
7
7
7
7
7
7
7
7
7
A
A
A
A
B
B
B
B
B
B
B
B
1
2
3
4
45
135
−45
135
45
V
II
V
I
19.3
0.0
18.9
7
c
5.2 respectively.
From these experimental observations, we
13.8
25.5
41.3
33.8
24.1
35.5
33.6
19.6
18.9
21.7
26.1
8.3
9.3
reasoned that excessive amounts of DMF or DMSO may greatly
weaken the intramolecular H-bonds in 7 and over-linearize its
7.2 otherwise crescent-shaped backbone to such an undesired
extent that the reactive amine and carboxylate groups at the
helical ends were placed distant from each other, making the
17.5 intramolecular ring closure reaction difficult to occur. In light
1
2
3
4
5
6
7
8
V
45
135
135
−45
−45
−135
−135
14.0
9.8
7.4
9.7
15.1
of this reasoning and on the basis of our current compu-
tational findings, we postulated that the use of lower but right
amounts of polar solvent might relax the H-bonding-rigidified
backbone to some good extent to allow the BOP group to come
a
Computational optimization and energy calculation were carried out
at the levels of B3LYP/6-31G(d,p) and B3LYP/6-311+G(2d,p) in the gas
phase, respectively. Relative energy was normalized based on 7A , the
2
b
c
most stable 7–BOP conjugate. Relative energy was normalized based in with ease and the ring closure reaction to take place more
on near-planar 7 (Fig. 2c).
efficiently, rather than over-linearize the backbone to impede
the macrocyclization reaction.
With the above hypothesis in mind, we evaluated the
pentameric backbone in type I (e.g., 7A ) and the most stable impact the way the organic base DIEA was added might have
4
type V (e.g., 7A
.3 and 26.1 kcal mol , respectively.
These computational results suggest that the energetic ponding monomer 1a over a period of four hours increases the
3
) intermediates are less stable than planar 7 by on the macrocyclization reaction. We found that slow addition
−
1
8
2 2
of DIEA into a CH Cl solution containing BOP and the corres-
penalty associated with induction of the H-bonding-rigidified yield of 1 by 5% to 30% (entry 2, Table 2). We also found that
planar pentameric backbone in 7 (Fig. 2c) into a distorted lowering the reaction temperature to 0 °C is not helpful either,
helical backbone as seen in various 7–BOP conjugates reducing the yield to 17% (entry 3, Table 2). Consequently, the
(
2
7
Table 1, Fig. 4 and S1–S4†) could amount to as high as subsequent screening using varying amounts of DMF, which
6.1 kcal mol− via the most stable type V intermediate (e.g., increase in small increments of 1–2.5%, were mostly con-
1
−
1
A3) or at least 8.3 kcal mol if the reaction occurs via the ducted via slow addition of DIEA over four hours at room
1
0
4
type I intermediate (e.g., 7A ) as proposed by Castro. Since
7A is less stable than 7A by 11.7 kcal mol , both might be
4 3
−1
the possible intermediates of the BOP-mediated coupling reac-
tion. The corresponding transition states, which are difficult to
assess here, could be even higher in energy. One possible
method to decrease this energetic penalty is to relax the rigid-
Table 2 Effects of DMF of varying percentages in CH
mediated one-pot preparation of pentamer 1 from monomer 1a
2 2
Cl on BOP-
a
b
Entry
% DMF in CH
Cl
2 2
Temperature
25 °C
Yield (%)
c
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
0%
0%
0%
25
30
17
34
36
36
35
35
39
47
38
37
29
40
39
0 °C
25 °C
2.5%
5.0%
7.5%
10%
12%
14%
15%
16%
18%
20%
15%
15%
1
1
1
1
1
1
30 °C
35 °C
Fig. 4 Structures of 7A
conformation from type II and V intermediates and of 7A
to type I intermediate. The structures shown at the bottom illustrate the
pentameric backbone of 7 in 7A –7A , respectively. Note that after com-
putational optimization, the O–N bond in BOP (Fig. 2a) breaks to
2
and 7A
3
that correspond to the most stable
a
Typical reaction conditions: DIEA (0.8 mmol) was added over a
4
that belongs
course of four hours into a solution (3 mL) containing 1a (0.2 mmol)
and BOP (0.4 mmol) under constant stirring. After addition, the reac-
tion mixture was stirred at a certain temperature for another 26 h.
2
4
b
c
Isolated yield by washing with CH
2 2
Cl and MeOH. DIEA was added
produce the PvO bond, releasing the neutral hexamethyl- in one pot instead of over four hours; this is the condition reported by
7c
phosphoramide group to generate neutral 7A
2
.
Zeng and his co-workers.
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temperature. Interestingly, while the yields of 1 remain similar We believe that this one-pot macrocyclization protocol should
at 34–36% when the percentage of DMF in CH Cl varies from enable facile access to a unique class of pentagon-shaped
2
2
2
.5 to 12%, such yields significantly increase to 39% in 14% pentavalent ligands that may promise some interesting appli-
2
a,9
DMF in CH
2
Cl
2
and reach as high as 47% in 15% DMF in cations in biology,
in addition to those already demon-
2
f,h,4b,8
CH Cl . After this, the yields decrease to 38, 37 and 29% with strated in chemistry.
2
2
2 2
the use of 16, 18 and 30% DMF in CH Cl as the reaction
medium, respectively. At higher temperatures, the yields also
decrease to 40% or lower (entries 14 and 15, Table 2). This
suggests the pentameric backbone in 7 to be more flexible at
Acknowledgements
higher temperatures than at 25 °C, placing the reactive amine Financial support for this work to H. S. and T. L. by the
and carboxylate groups farther away from each other and Singapore National Research Foundation under its
decreasing the ring closure reaction extent.
Environment and Water Research Programme and adminis-
Although additional screening of other polar solvents does tered by PUB is acknowledged.
not result in improved macrocyclization efficiencies (Table 3)
when compared to DMF, the obtained yields of 19–28% are
7
c
still significantly better than those previously reported.
Notes and references
Among the polar solvents studied, THF, acetonitrile and
DMSO produce more of 1 than acetone and NMP by 6–9%.
Using the above optimized one-pot macrocyclization con-
ditions, pentamers 2 and 3 (Fig. 1) were produced in respective
yields of 29% and 13%, which are better than 18% and 10% as
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7
c
reported previously. For one-pot synthesis of 4–6, 6 ml, rather
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7
c
1
6%, respectively. The satisfactory preparations of 1–6 estab-
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rapid and efficient production of other closely related
pentamers.
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pot synthesis protocol that allows for significantly more
efficient production of macrocyclic pyridone-based aromatic
pentamers with yields as high as 47%. More specifically, the
computationally elucidated energetic penalty accompanying
the formation of 7–BOP conjugates can be effectively mini-
mized via the use of a carefully optimized appropriate amount
of polar DMF, which helps to relax the otherwise highly rigidi-
fied pentameric backbone to just the right extent that in turn
maximally increases the intramolecular ring closure efficiency.
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a
one-pot preparation of pentamer 1 from monomer 1a
b
Entry
15% co-solvent in CH
2
Cl
2
Yield (%)
1
2
3
4
5
THF
28
27
26
20
19
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a
Typical reaction conditions: DIEA (0.8 mmol) was added over a
course of four hours into a solution (3 mL) containing 1a (0.2 mmol)
and BOP (0.4 mmol) under constant stirring. After addition, the reac-
(
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Isolated yield by washing with CH
2 2
Cl and MeOH. NMP = N-methyl-2-
pyrrolidone.
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