Knotaxanes - Rotaxanes with knots as stoppers

Article abstract of DOI:10.1002/anie.200351981

Get knotted: Molecular knots have been used as stoppers in the assembly of "knotaxanes", a new family of topologically chiral rotaxanes (see picture). Two knotaxanes were separated into enantiomers using HPLC with a chiral stationary phase and characteriz

Full text of DOI:10.1002/anie.200351981

Communications
Knotaxanes
Knotaxanes—Rotaxanes with Knots as
Stoppers**
Oleg Lukin, Takateru Kubota, Yoshio Okamoto,
Frauke Schelhase, Albena Yoneva, Walter M. Müller,
Ute Müller, andFritz Vögtle*
Dedicated to Professor Karl Heinz Dötz
on the occasion of his 60th birthday
In a recent report[1] we coined the name “knotaxane” for a
challenging, yet hitherto unknown, hypothetical type of
compound: a rotaxane in which the stoppers are molecular
knots. Here we report the first successful synthesis of two
members of this new topological family and their chiral
resolution. Interest in this species comes on the one hand
from their topological chirality,[2] since unlike having just a
stereocenter, as in classical stereochemistry, the whole nano-
sized molecular skeleton is chiral (“nanochiral”). Their
chirality, therefore, should be quite pronounced,[3] and
strong chiroptic effects and chiral inductions are expected.
The use of the rotaxane platform,[2,4,5] on the other hand,
makes such an assembly a particularly attractive architecture
with an option to control the direction[6] of rotation or the
shuttling[4c] of mechanically linked constituent parts.
[*] Prof. Dr. F. Vögtle, Dr. O. Lukin, Dipl.-Chem. F. Schelhase,
Dipl.-Chem. A. Yoneva, W. M. Müller, U. Müller
KekulØ-Institut für Organische Chemie und Biochemie
Rheinische Friedrich-Wilhelms-Universität Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
Fax: (+49)228-735-662
E-mail: voegtle@uni-bonn.de
Dr. T. Kubota, Prof. Dr. Y. Okamoto
Department of Applied Chemistry
Graduate School of Engineering
Nagoya University
Chikusa-ku, Nagoya 464-8603 (Japan)
[**] Financial assistance by the Deutsche Forschungsgemeinschaft is
gratefully acknowledged (Sonderforschungsbereich 624). O.L.
thanksthe Alexander von Humboldt Foundation for a fellowship.
We would also like to thank Dipl.-Chem. S. Bitter, Dipl.-Chem. J.
Brüggeman, and Dipl.-Chem. R. Henkel for recording MALDI-TOF
mass spectra.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200351981
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Our previous efforts[1] showed that in spite of the
significant achievements reached in the synthesis and deriva-
tization of knotanes, the preparation of higher covalently
linked knotanes meets severe difficulties, since such a syn-
thesis implies the availability of selectively functionalized
molecular knots, the preparation of which is once again
difficult.[1,7,8] Our first attempt at the synthesis of a knotax-
ane[1] by the phenolate-trapping method[9] proved unsuccess-
ful because of the partial decomposition of 1 in the basic
solution.
and the low yield of 3 suggested that the lack of knotaxane
formation are a consequence of the voluminous size of the
knot stoppers and the shortness of the isophthaloyl linkage,
which prohibits the threading of 2.
Therefore, we designed an elongated axle 4 which,
according to preliminary molecular modeling studies, could
efficiently thread the macrocycle 2 and prevent noticeable
overcrowding of the mechanically bound parts both in the
transition state and the final assembly. Acylation of aniline
with isophthaloyl chloride and sulfochlorination of the
resulting isophthaloyldiphenyldiamide with chlorosulfonic
acid accomplished the synthesis of 4. The reaction of
monohydroxy-knotane 1 with disulfonyl chloride 4 afforded
the dumbbell 5a and the desired knotaxane 6a in yields of 55
and 19%, respectively. The structures of 5a and 6a were
proved by means of MALDI-TOF mass spectrometry and 1H
NMR spectroscopy. The application of different ionization
conditions in the former experiment enabled the observation
of either signals corresponding to the molecular ion peaks
only or characteristic fragmentation patterns brought about
by the cleavage of the sulfonic esters. The appearance of a
signal corresponding to the molecular ion of 2 (M+ = m/z 997)
in the MALDI-TOF spectrum of 6a at higher ionization
potentials leaves no doubts about an efficient mechanical
connection between the constituent parts of the knotaxane.
1
The H NMR spectra of 5a and 6a recorded in [D6]DMSO
show the amide signal pattern that is typical for mono-O-
1
sulfonylated knotanes.[1] The other signals in the H NMR
spectra are also in line with the assignments that were recently
reported by us.[11]
The expected d,l pairs of the knotaxane 6a and the
dumbbell 5a were separated on noncommercial “Chiralpak
AD” column material[12] containing tris(3,5-dimethylphenyl-
carbamoyl)amylose covalently linked to the silica gel support.
Figure 1 shows that the enantiomers of 5a and 6a can be
successfully separated. The chromatogram of 6a reveals,
however, a few peaks of impurities which reflects the
difficulties in the preparative purification of 6a. The
MALDI-TOF mass spectra shown in Figure 2 confirm the
successful purification and enantiomeric separation of kno-
taxane 6a. The identification of the meso forms of both 5a
and 6a is a major difficulty. In both cases the fractions of the
An alternative method for the synthesis of amide-type
rotaxanes,[10] which relies on the hydrogen-bond-templated
threading of various dicarboxylic acid chlorides through
cyclic tetraamides and offers mild reaction conditions, now
turned out to be of advantage. The reaction of monohy-
droxy-knotane 1 with isophthaloyl chloride in the presence
of the macrocycle 2, however, yielded no rotaxane and only
17% of dumbbell 3. The examination of molecular models
Figure 1. a) Separation of the enantiomersof 5a (column: Chiralpak AD, eluent:
hexane/chloroform (30/70), CD detection at 254 nm); b) separation of the enan-
tiomersof 6a (column: Chiralpak AD, eluent: hexane/chloroform/isopropanol
(60/40/3), CD detection at 254 nm).
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Communications
properties necessitates, therefore, a knotane bearing two
dansyl and one hydroxy group. For this purpose we have used
dihydroxyallyloxy-knotane 7, the isolation of which in the
pure form is reported here for the first time. Sulfonylation of 7
with dansyl chloride followed by removal of the allyl group
from the intermediate 8a with Bu3SnH readily gives the
desired monohydroxy-knotane 8b. The new knotaxane 6b,
which was synthesized from 8b by a similar method as
described for the preparation of 6a, has been isolated in 20%
yield. The purification of 6b by chromatography on silica gel
was indeed found to be easier than that of 6a. HPLC analysis
together with the 1H NMR and MALDI-TOF spectra
revealed the high purity of 6b. Unlike its analogue 6a,
knotaxane 6b was found to exhibit excellent solubility in
alcohols. The latter property allowed us to achieve the
separation of enantiomers of 6b by HPLC using a commercial
noncovalent Chiralcel OD material.[13] Figure 4 shows the
circular dichrograms of the isolated enantiomers of 6b.
Similar to the case of 6a, the fractions of the meso forms of
6b showed overlap with those of the enantiomers.
Figure 2. Sectionsof the MALDI-TOF spectra of fractions1 and 2 of
6a (matrix: 2,4,6-trihydroxyacetophenone).
meso forms show significant overlap with those of the
enantiomers. The circular dichroism spectra of the enantiom-
ers of 5a and 6a, recorded after preparative separation
(Figure 3), reveals that the sulfonamide ring in the rotaxane
only modifies the chiroptical properties of the dumbbell
slightly.
The poor solubility and the ensuing purification and
separation difficulties of the first member of the knotaxane
family (6a) prompted us to develop new knotted stoppers. We
recently showed that the solubility of knotanes can be
efficiently tuned by introduction of specific substituents
such as FrechØt-type dendrons[9] and phosphoryl groups[11] at
the outer edges of knotanes. The introduction of 5-(dimethyl-
amino)naphthalenesulfonyl (dansyl) groups combining both
lipophilicity and polarity seems attractive in this respect. The
preparation of a new knotaxane with improved solubility
Figure 4. Circular dichroism spectra of enantiomers of knotaxane 6b
(d=0.1 mm, CF3CH2OH).
The successful synthesis of the first knotaxanes demon-
strates the advances made in synthetic chemistry in regard to
such topological compounds. For the first time we have three
topological stereogenic units held together both in an
interlocked and covalent manner. Scheme 1 shows the
analogy of the chirality designation of the topological dumb-
bell and knotaxane with the description of the stereo-
chemistry of open-chain sugar acids developed by Emil
Fischer in 1891.[14]
The topological chirality of the knotaxanes com-
bined with their size, which exceeds 6 nm (Figure 5),
makes such systems similar to natural macromolecular
machines such as multi-enzyme complexes.[15] As a
consequence of its Cs symmetry, sulfonamide macro-
cycle 2[16] should exhibit a unidirectional rotation in the
enantiomeric forms of the knotaxanes 6a,b (Scheme
1). The detection of such a rotation would be an
interesting challenge for AFM/STM techniques. Our
next goal is to synthesize knotaxanes containing more
than one wheel on the axle, to make the sugar-type
skeleton (Scheme 1) longer, and to elucidate how the
topological chirality is tuned.
Figure 3. Circular dichroism spectra of a) dumbbell 5a (d=0.1 mm, CHCl3), and b) kno-
taxane 6a (d=0.1 mm, CHCl3).
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Scheme 1. Analogy of topological descriptors in chiral dumbbells (for
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*
*
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Figure 5. MMX energy-minimized model of knotaxane 6 (CPK surface
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Keywords: chiral resolution · circular dichroism ·
molecular devices· rotaxanes
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