Synthesis of multivalent host and guest molecules for the construction of multithreaded diamide pseudorotaxanes

Article abstract of DOI:10.3762/bjoc.8.24

A series of di-, tri- and tetravalent axles and wheels for the synthesis of pseudorotaxanes bearing the tetralactam macrocycle/diamide axle binding motif was prepared. Starting from iodinated monovalent precursors, Sonogashira cross-coupling reactions wer

Full text of DOI:10.3762/bjoc.8.24

Synthesis of multivalent host and guest molecules
for the construction of multithreaded
diamide pseudorotaxanes
Nora L. Löw‡1, Egor V. Dzyuba‡1, Boris Brusilowskij‡1, Lena Kaufmann1,
Elisa Franzmann2, Wolfgang Maison2, Emily Brandt3,4, Daniel Aicher3,5,
Arno Wiehe1,3 and Christoph A. Schalley*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 234–245.
1Institut für Chemie und Biochemie der Freien Universität Berlin,
Takustr. 3, 14195 Berlin, Germany, 2Pharmazeutische und
Medizinische Chemie, Universität Hamburg, Bundesstr. 45, 20146
Hamburg, Germany, 3Biolitec research GmbH, Otto-Schott-Str. 15,
07745 Jena, Germany, 4Charité – Universitätsmedizin, International
Graduate Program Medical Neurosciences, Charitéplatz 1, 10117
Berlin, Germany and 5WITEGA Laboratorien Berlin-Adlershof GmbH,
Magnusstr. 11, 12489 Berlin, Germany
doi:10.3762/bjoc.8.24
Received: 21 November 2011
Accepted: 23 January 2012
Published: 09 February 2012
This article is part of the Thematic Series "Supramolecular chemistry II".
Associate Editor: N. Sewald
Email:
Christoph A. Schalley* - christoph@schalley-lab.de
© 2012 Löw et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author ‡ Equal contributors
Keywords:
multivalency; pseudorotaxanes; Sonogashira coupling;
supramolecular chemistry; tetralactam macrocycles
Abstract
A series of di-, tri- and tetravalent axles and wheels for the synthesis of pseudorotaxanes bearing the tetralactam macrocycle/
diamide axle binding motif was prepared. Starting from iodinated monovalent precursors, Sonogashira cross-coupling reactions
were utilized to couple the binding sites to appropriate spacer groups. Through this “Lego” or “toolbox” approach, the convergent
synthesis of host and guests with a well-defined number of the binding sites is possible. In addition, the spatial arrangement of the
binding sites can be controlled through the quite rigid connections between linker and binding sites. Although a quantitative assess-
ment of binding strengths was not possible by NMR titration experiments, typical and significant shifts of the signals of the diamide
moiety indicate qualitatively the formation of pseudorotaxanes from the axle and wheel precursors.
Introduction
Synthetic supramolecular complexes have the great potential to but also self-assembly, self-sorting, templation and multivalent
put those concepts to the test that govern much of the noncova- binding [1-8]. Consequently, the reductionist investigation of
lent chemistry in nature. Among these concepts are not only synthetic supramolecules can help us to understand biological
molecular recognition and the noncovalent bonds themselves, systems better. Such a synthetic approach can also help in the
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investigation of multivalent binding [9-12], because the number binding properties. Among the examples of such multivalent
of binding sites can be altered at will, and studies can be done pseudorotaxanes [80-82], the “molecular elevators” reported by
with a suitable series of host and guest molecules in which the Stoddart et al. [83,84] are particularly fascinating, because they
nature and number of binding sites is systematically varied.
combine multivalency with the ability of a molecular device to
respond to external stimuli, in this case to acids and bases,
Interlocked molecules [13-28] are interesting not only because which induce motion of the wheel and axle components rela-
of their particular topology or the mechanical bond, but also as tive to each other.
they have been intensely investigated with respect to the
construction of molecular machines [29-32]. The mechanical Tetralactam macrocycles (TLMs) [65,66] have widely been
bond appears particularly suited for this goal, because it used in the synthesis of amide catenanes and rotaxanes [85-92]
connects the axle and wheel strongly, but leaves freedom for the and represent excellent hosts for dicarbonyl compounds [93-
relative movement of the two components. Pseudorotaxanes are 101]. They bear four converging amide groups, which in each
the precursors for both rotaxane syntheses by stoppering reac- case can form hydrogen bonds to suitable axle molecules in
tions or catenanes by macrocyclization. The use of weak inter- aprotic and not too strongly competitive solvents such as
actions, e.g., metal complexation [33-47], charge-transfer inter- CH2Cl2 or CHCl3. In this contribution, we report the synthesis
actions [48-63], or hydrogen bonding [64-79], between the and binding behaviour of di-, tri- and tetravalent diamide-
single building blocks is necessary for efficient templating axle–TLM complexes. The design is based on the two building
effects, which aim at assembling higher-order molecular archi- blocks 1 and 2 (Figure 1). Compound 1 is the wheel component,
tectures. The synthesis of a multiply threaded architecture and 2 is the axle, which comprises a diamide moiety that binds
[80,81] thus requires multivalent wheel and axle components as to the wheel as indicated in the center of Figure 1 through the
precursors, which are also interesting with respect to their formation of four (wheel)N–H···O=C(axle) hydrogen bonds.
Figure 1: Hunter/Vögtle-type tetralactam macrocycle 1 bearing an iodo substituent at one of the isophthaloyl groups, and the diamide axle piece 2.
The iodoaryl groups in both building blocks are suitable for Sonogashira cross-coupling reactions. Therefore, these monovalent precursors can be
connected to different suitable spacers so that a "toolbox" of multivalent hosts and guests can be synthesized convergently. The center shows the
binding motif, which connects the axle and wheel by four N–H···O hydrogen bonds.
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Through the iodine substituents, both building blocks can be tuted TLM 1 was prepared according to well-documented litera-
connected to appropriate spacers in Sonogashira cross-coupling ture procedures [64-103] and used for the cross-coupling reac-
reactions [102].
tions in this study.
This coupling strategy creates rather rigid connections to the The synthesis of the iodo-substituted monovalent diamide axle
spacers and helps in reducing the entropic penalties that arise centerpiece 2 was realized by the four-step synthesis shown in
from conformational fixing of the spacers upon multivalent Scheme 1. The free amino group in mono-Cbz-protected N,N'-
binding. The building blocks were chosen based on simple dimethylethylene diamine 3 [105] was elongated with the
force-field calculations of the resulting pseudorotaxanes and commercially available N-Boc-protected β-alanine 4 in the pres-
permit us to synthesize a series of different hosts and guests in a ence of EDC and HOBt as activating coupling reagents. This
convergent way. Thus, a "toolbox" [103,104] of multivalent step provides the basis for future stopper attachment to the axle
host and guest molecules becomes available with this synthetic termini, as mentioned above. Product 5 was formed with a yield
strategy. In the future, the pseudorotaxanes designed here of 92% without the need for time-consuming purification steps.
should be easily converted into rotaxanes after cleavage of the This molecule now contains two orthogonal protecting groups,
Boc protective group at the axle ends and attachment of stopper and hydrogenation of 5 deprotects the amino group at the
groups to the terminal amines.
N,N'-dimethylethylene diamine site to yield 6 in 98% yield.
The iodo-substituted acid 8 can easily be prepared under mild
conditions from the iodine-free precursor 7 [106] by using I2
and phenyliodine diacetate (PIDA) and is then available for
Results and Discussion
Synthesis of monovalent precursors
Although aryl bromides, triflates and sometimes even chlorides amide coupling with 6 yielding binding site 2 in 73% yield.
react efficiently in Sonogashira cross-coupling reactions, our Since an excess of 7 was used and the 2’/6’-positions are steri-
previous studies [103,104] showed that only the iodinated TLM, cally hindered, only monoiodination in the 4’-position was
and in some rare cases the corresponding triflate-substituted observed. This synthetic pathway thus gives reasonable overall
wheel, is reactive enough to provide sufficiently high yields. yields.
This is particularly important when the same precursor is to be
multiply connected to the same spacer. Low-yielding reaction It should be mentioned that the diamide moiety bears two
steps would result in mixtures of the desired compounds with tertiary amides. All attempts to prepare a similar axle with sec-
incompletely substituted side products. Therefore, iodo-substi- ondary amide groups failed because of the low solubility of the
Scheme 1: Synthesis of the monovalent diamide axle 2, which was used for Sonogashira coupling to the appropriate spacers: (a) EDC, HOBt, DMF,
22 h, 92%; (b) H2, Pd/C, EtOH, 3 d, 98%; (c) EDC.HCl, HOBt, DMF, 24 h, 73%; (d) I2, PIDA, AcOH/Ac2O, 1 h, 67%; (EDC = 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide, HOBt = 1-hydroxybenzotriazole, DMF = N,N'-dimethylformamide, PIDA = phenyliodine diacetate).
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products. This is an important aspect, because the threading of equilibrium between (trans,trans)-, (trans,cis)- and (cis,cis)-
the station into the TLMs requires noncompetitive solvents such isomers in solution, which complicates the analysis of the
as CH2Cl2 or CHCl3. Consequently, any polar aprotic solvent, binding properties.
such as acetone, acetonitrile, DMF or DMSO, which would
solubilize the axles sufficiently well, would interfere strongly Synthesis of multivalent wheels
with pseudorotaxane formation. The tertiary amides are much Monovalent axle 2 and TLM 1 are designed to give a good
more soluble and, therefore, appear to be the more appropriate complementary fit, when both are connected to the same flat
binding site. However, the better solubility comes at a price. spacer molecules through Sonogashira cross-coupling reactions.
While secondary amides prefer the trans-conformation, in Therefore, ethynyl-substituted benzene spacers 9, 11 and 13
which the carbonyl oxygen and the NH proton diverge, the were used to synthesize a bent divalent (10), a linear divalent
tertiary amides do not exhibit a similarly strong preference for (12), and a trivalent wheel (14) [103] (Scheme 2 and
one of the conformations. The axle binding sites thus exist in Scheme 3). From the enormously broad choice of different
Scheme 2: Synthesis of divalent wheels from TLM 1: (a), (b) (Ph3P)2PdCl2, CuI, PPh3, NEt3, DMF, 25 °C, 24 h, 90% (10), 78% (12).
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Scheme 3: Synthesis of trivalent wheel 14 from TLM 1: (a) (Ph3P)2PdCl2, CuI, PPh3, NEt3, DMF, 25 °C, 24 h, 40% (14). Compound 14 was
described previously [103] and is included to complete the series.
Pd-catalysts and reaction conditions, we used (Ph3P)2PdCl2 and procedure [107,108] employing Pd2(dba)3 as the catalyst and
CuI in the presence of PPh3 as the coligand, NEt3 as the base, AsPh3 as the coligand in NEt3/DMF was applied (Scheme 4).
and DMF as the solvent. This protocol was successfully applied This reaction unfortunately provided only 7% of the desired
previously for the synthesis of 14 [103]. The yields of 90% and tetravalent wheel 16; however, this amount sufficed for charac-
78% obtained for the divalent hosts 10 and 12, respectively, terization by 1H NMR and ESI mass spectrometry. There may
were even higher than that for 14 (40%).
be several reasons for this observation. One reason for the low
yield may be solubility, which in our experience is always low
All attempts to use the same conditions for the fourfold for tetralactam wheels connected through nicely stacking
coupling of 1 to 15 to synthesize tetravalent wheel 16 were spacers.
unsuccessful, and we finally used another procedure for the
cross-coupling reaction [107]. Because the Cu(I) catalyst may Synthesis of multivalent axles
interfere with the Zn core of porphyrin 15 or lead to Glaser In order to prepare the multivalent axles that fit to the wheels
coupled side-reaction products, a copper-free Sonogashira described above, the same spacers 9, 11 and 13 were also used
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Scheme 4: (a) Pd2(dba)3, AsPh3, NEt3, DMF, 120 °C, 12 h, 7% (16).
for the synthesis of multivalent guests 17–19, respectively (Scheme 6) and yielded 17% of the product. Interestingly, a
(Scheme 5). In addition, a triethynyl-adamantane derivative 20 homocoupling of axle 2 gave rise to divalent axle 22, which was
[109,110] was employed in order to prepare an axle component isolated as a side product in 37% yield. This molecule may be
with a slightly different, nonflat spacer geometry.
useful for other divalent hosts, such as two macrocycles
connected through a butadiyne spacer or a thiophene unit. Such
For the axle preparation, neither the use of (Ph3P)2PdCl2/CuI/ hosts have been reported previously [103] and are not included
PPh3 nor that of Pd2(dba)3/AsPh3 provided the desired prod- here.
ucts, and therefore the conditions of the Sonogashira cross-
coupling reactions had to be optimized again. Finally, the mix- Formation of pseudorotaxanes
ture of Pd2(dba)3/CuI/PPh3 gave the di- and tritopic axles 17–19 In order to determine the binding strengths quantitatively, NMR
and 21 in DMF/NEt3 with decent yields when the temperature titrations, dilution experiments, and ITC experiments were
was raised to 70 °C. The copper-free Sonogashira procedure attempted. The NMR titrations suffer from the fact that different
was again applied for the synthesis of tetravalent guest 23 conformations of the tertiary amide groups hamper an in-depth
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Scheme 5: Synthesis of a series of multivalent guests starting from the axle 2. (a), (b), (c), (d): Pd2(dba)3, CuI, PPh3, NEt3, DMF, 70 °C, 3 d; 32%
(17), 37% (18), 24% (19), 64% (21), respectively.
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Scheme 6: Synthesis of the tetravalent axle 23 and its divalent side product: (a) Pd2(dba)3, AsPh3, NEt3, DMF, 80 °C, 2 d, 37% (22), 17% (23).
evaluation of the titration data. The diamide N-CH3 and N-CH2 mass spectrometry was attempted in order to show the forma-
protons appear with four sets of signals, one for the tion of 1:1 complexes qualitatively, but this was without
(trans,trans)-, two for the asymmetric (trans,cis)- and one for success. This does not come as a surprise in view of previous
the (cis,cis)-isomer. This, and significant signal overlaps, make theoretical calculations on amide/tetralactam macrocycle
it impossible to quantify the NMR titration data. For ITC complexes [111], which show that simple amide axles dethread
measurements, the concentration range in which one can expect in the gas phase because of a favourable entropy term arising
reasonable heats to evolve upon binding could not be reached, from the increase in particle number upon complex dissociation.
due to the low solubility of the wheel components. Furthermore, This entropic contribution overcompensates for the enthalpic
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Beilstein J. Org. Chem. 2012, 8, 234–245.
contribution to the binding. As the calculations were done for
monovalent complexes and monoamide, we nevertheless
attempted to ionize complexes of our di- and trivalent systems,
but unfortunately without success.
However, when 1H NMR spectra of the free axles are compared
with the 1H NMR spectra of 1:1 mixtures of axles and wheels,
structure-indicative signal shifts are observed that demonstrate
the axles to be threaded through the wheels (Figure 2). Conse-
quently, the binding event cannot easily be quantified, but there
is qualitative evidence for pseudorotaxane formation. With
1H/1H-COSY NMR experiments, an assignment of, for
example, the N-CH3 groups to two singlets at ca. 3.1 ppm is
possible (protons labelled “1” in the spectra of 17, 18 and 19 in
Figure 2). These signals shift to higher field by ca. 0.9 ppm
when 1 equiv of the wheel component is added. These com-
plexation-induced signal shifts are even stronger than similar
shifts observed for other rotaxanes with a diamide moiety [101].
The fact that proton “3” also shifts significantly indicates that
binding may also involve the carbonyl group of the Boc protec-
tive group. A reversible shuttling between both the diamide
station and the outer carbonyl group of that moiety and the Boc
group would rationalize this shift easily. Consequently, this
preliminary NMR evidence qualitatively provides evidence for
binding, while a quantification is not easily possible.
Conclusion
In conclusion, the synthesis of a "toolbox" of multivalent host
and guest molecules has been described, which can be obtained
from the two easy-to-prepare building blocks 1 and 2 by Sono-
gashira coupling reactions to ethynyl-substituted spacers. This
synthetic approach is convergent, and thus the sometimes
limited yields do not detract from this approach. With our
toolbox, the number and position of binding sites can be varied
systematically; hence, the toolbox provides a means to examine
multivalency. However, despite the fact that there is qualitative
evidence for pseudorotaxane formation, the binding motif is not
yet optimal for a quantitative study. Two problems need to be
solved: On one hand, the solubility of the hosts needs to be
increased such that a concentration range can be reached that
enables us to obtain thermochemical data from ITC experi-
ments. On the other hand, a more suitable binding moiety would
be advantageous for use in the axles. The tertiary amides
obscure a precise analysis of NMR titrations because of the
interconverting trans and cis amide conformations. Secondary
amides again cause solubility problems. However, as described
in a recent article [112], diketopiperazines are quite tightly
bound to the TLMs. Equipping our wheels with better solubi-
lizing groups and using diketopiperazine axles should therefore
help us to go beyond the limitations encountered in the present
study.
Figure 2: Aliphatic regions of the 1H NMR spectra (CD2Cl2, 500 MHz,
298 K, 2.3 mM) of (a) 10 (top), 17@10 (center) and 17 (bottom), (b) 12
(top), 18@12 (center) and 18 (bottom), and (c) 14 (top), 19@14
(center) and 19 (bottom). Because of the low solubility of the wheel
components 10, 12 and 14, the samples were dissolved in CD2Cl2/
CD3OD (10:1). Red letters assign signals of the wheels as shown in
Scheme 2, green numbers those of the axles as shown in Scheme 5.
Supporting Information
Supporting Information File 1
Experimental details and characterization data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-24-S1.pdf]
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Acknowledgements
This research was funded by the Deutsche Forschungsgemein-
schaft (SFB 765 "multivalency") and the Fonds der Chemischen
Industrie (FCI). E.V.D. and L. K. thank the Studienstiftung des
deutschen Volkes for a PhD scholarship. We thank Gülsah
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