An efficient approach to mechanically planar chiral rotaxanes

Article abstract of DOI:10.1021/ja412715m

We describe the first method for production of mechanically planar chiral rotaxanes in excellent enantiopurity without the use of chiral separation techniques and, for the first time, unambiguously assign the absolute stereochemistry of the products. This proof-of-concept study, which employs a chiral pool sugar as the source of asymmetry and a high-yielding active template reaction for mechanical bond formation, finally opens the door to detailed investigation of these challenging targets.

Full text of DOI:10.1021/ja412715m

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An Efficient Approach to Mechanically Planar Chiral Rotaxanes
Robert J. Bordoli and Stephen M. Goldup*
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, U.K.
S
* Supporting Information
ABSTRACT: We describe the first method for produc-
tion of mechanically planar chiral rotaxanes in excellent
enantiopurity without the use of chiral separation
techniques and, for the first time, unambiguously assign
the absolute stereochemistry of the products. This proof-
of-concept study, which employs a chiral pool sugar as the
source of asymmetry and a high-yielding active template
reaction for mechanical bond formation, finally opens the
door to detailed investigation of these challenging targets.
s every chemistry student learns, molecular chirality can
arise not only as a result of a tetrahedral carbon atom with
A
four nonequivalent substituents but also due to elements of axial,
planar, or helical chirality.1 It is less commonly appreciated that
interlocked molecules can display optical activity as a direct result
of the mechanical bond, even when the individual components
are devoid of covalent chirality; for example, a [2]rotaxane in
which the two ends of the thread are nonequivalent and the
macrocycle is rotationally unsymmetrical (e.g., rotaxanes V,
Figure 1) exists as a pair of enantiomers, depending on the
relative orientation of macrocycle and thread.2−4
Figure 1. Schematic of our proposed approach to mechanically planar
chiral rotaxanes. Stereochemical labels are arbitrary.
Vogtle et al. achieved the first isolation of such mechanically
̈
planar chiral [2]rotaxanes,5,6 and subsequently [1]-7 and
[3]rotaxanes,8 in high enantiopurity using chiral stationary
phase (CSP) HPLC to separate a racemic mixture of products.
Studies on the resolved materials revealed high molar circular
dichroism (CD), indicative of a well-expressed chiral environ-
ment.9 Later Kameta and Hiratani et al. employed a racemic
mixture of mechanically planar chiral [2]rotaxanes to show that
the environment formed between the thread and macrocycle can
act as an effective chiral field for sensing applications.10
that does not affect the stereochemistry of the mechanical
bond,15 would then give enantiopure rotaxanes V. Although
separation of such mechanical diastereoisomers had not
previously been reported,16−19 we recently observed the efficient
transfer of chiral information between a chiral stopper unit and
an achiral macrocycle in a sterically crowded rotaxane.20 We
hypothesized that such efficient chiral information transfer would
lead to mechanical diastereoisomers based on our “small”
macrocycles to display significantly different physical properties
and thus be separable using standard chromatographic methods.
Here we report a proof-of-concept study that demonstrates
our new approach to these challenging molecules is not only
feasible but extremely efficient, allowing access to a mechanically
planar chiral rotaxane in high enantiopurity without the need for
chiral separation techniques. Our approach also permitted us, for
the first time, to assign the absolute stereochemistry of our
separated mechanically planar chiral rotaxanes.
Despite these early successes, the synthesis of mechanically
planar chiral rotaxanes remains an unsolved problem; the only
enantioselective approach delivered the product in just 4% ee.11
Thus, to date, all syntheses of enantiopure materials have relied
on preparative CSP-HPLC, which necessarily limits access to
these intriguing molecules.12 With a view to opening up
mechanically planar chiral rotaxanes to investigation in
applications such as catalysis, host-guest chemistry, materials,
and sensors, we set out to develop a simple method for their
production using standard synthetic techniques.
We proposed an approach based on separating the mixture of
diastereoisomeric [2]rotaxanes possessing the same covalent
configuration but with opposite mechanical configuration (rotax-
anes IV, Figure 1) that would result from an active template
coupling of half-threads I and III mediated by macrocycle II.13,14
Substituting the chiral unit of the separated mechanical
diastereoisomers IV with an achiral stopper unit, in a manner
When rotationally unsymmetrical macrocycle 2 was employed
in an active template copper-catalyzed azide-alkyne cyclo-
addition (AT-CuAAC)13b,20 with alkyne 1 and chiral azide 3
1
(Scheme 1), H NMR analysis of the crude reaction mixture
indicated near complete conversion (>95%) of the macrocyclic
component to a mixture of two interlocked products. Pleasingly,
Received: December 14, 2013
Published: February 22, 2014
© 2014 American Chemical Society
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Scheme 1. AT-CuAAC Synthesis of Mechanically
a
Diastereoisomeric Rotaxanes 4
1
Figure 3. Partial H NMR (600 MHz, CDCl3, 300 K), with selected
signals assigned, of (i) macrocycle 2, (ii) (D,Rmp)-4, (iii) (D,Smp)-4, and
(iv) their corresponding non-interlocked thread. See the Supporting
Information for full assignment. Labeling is as shown in Scheme 1.
Residual solvent signals are shown in gray.
a
1 equiv 2, 1.5 equiv each 1 and 3, 0.96 equiv [Cu(MeCN)4]·PF6, and
b
10 equiv NEtiPr2. Isolated yield after flash chromatography.
unit and R/Smp refers to the mechanical planar chirality resulting
from the orientation of the ring.23
1
The CD (Figure S1) and H NMR (Figure 3) spectra of
rotaxanes 4 are significantly different, reflecting the expected
strong interplay of the mechanical and covalent sources of
chirality. Furthermore, with the caveat that solid-state structures
are not necessarily representative of solution-state co-conforma-
tions, the non-covalent interactions observed by X-ray
crystallography (Figure 2) provide surprisingly good explan-
ations for some of the key differences in the 1H NMR spectra of
rotaxanes 4.24 Most strikingly, the signals corresponding to He
appear as well-separated doublets in 5.86 and 3.63 ppm in the
Figure 2. X-ray structures of (a) (D,Rmp)-4 and (b) (D,Smp)-4. Selected
distances (Å): (i) 2.9, (ii) 2.5, (iii) 2.5, (iv) 2.3, and (v) 2.6.
R
mp isomer and 6.31 and 4.88 ppm in the Smp compound. In both
simple column chromatography on silica gel separated the
mechanically interlocked products, which were unambiguously
identified as mechanically diastereoisomeric rotaxanes 4 by
single-crystal X-ray diffraction (XRD) (Figure 2). The two
diastereoisomers were isolated in 43% and 45% yield, a combined
isolated yield of mechanical bond formation of 88%. With
samples of both diastereoisomers in hand, we examined the
crude reaction mixture to reveal that they were formed in an
equimolar ratio, in keeping with their isolated yields.
Unfortunately, lowering the reaction temperature (20 °C) or
varying the solvent employed (THF, MeCN, PhMe, CHCl3,
EtOAc) did not lead to any observed diastereoselectivity.23
Single-crystal XRD analysis of rotaxanes 4 allowed us to
directly observe the relative orientation of macrocycle and thread
and assign the absolute stereochemistry of the mechanical
bond.22 To determine the mechanical stereochemistry, we assign
atom priorities A→D based on the Cahn−Ingold−Prelog system
as shown for (D-Smp)-4, where A is the highest priority atom in
the thread and B is the highest priority point of difference in its
ligands; atoms C and D are assigned similarly in the macrocycle.
The molecule is then viewed along the A→B axis: if atoms C and
D are disposed clockwise the stereochemistry is assigned as R; if
atoms C and D are disposed anticlockwise the stereochemistry is
assigned as S. Thus, the late-eluting diastereoisomer is assigned
as (D,Rmp)-4 and the early-eluting diastereoisomer as (D,Smp)-4,
where “D” refers to the covalent stereochemistry of the glucose
cases, their X-ray structures suggests that one He is engaged in a
CH−N hydrogen bond with a bipyridine nitrogen, with the
CH−N contact in (D,Smp)-4 (2.3 Å) significantly shorter than for
(D,Rmp)-4 (2.9 Å), which correlates with the larger relative
deshielding of He in the Smp diastereoisomer. Similarly, the large
relative shielding of one He in (D,Rmp)-4 (Δδ = 1.65 ppm)
compared with the non-interlocked thread can be tentatively
attributed to a close CH−π contact (2.5 Å) with the flanking
aromatic ring that is not present in the X-ray structure of the Smp
isomer (Δδ = 0.37 ppm). The X-ray structures also indicate that
the deshielded He that participates in the CH−N hydrogen bond
with the bipyridine nitrogen is He(S) in (D,Rmp)-4 but He(R) in
(D,Smp)-4. Thus, the relative shift of the diastereotopic protons
He in the two mechanical diastereoisomers is large: Δδ = 2.68
and 0.98 ppm for He(R) and He(S), respectively.
Having separated and fully characterized diastereoisomeric
rotaxanes 4, we turned our attention to substituting the chiral
glucose unit by an achiral amine. Although such substitution
reactions of esters have previously been reported in rotaxane
substrates under mild conditions,15b,c,e in the case of rotaxanes 4
they were unsuccessful, presumably due to the unactivated
nature of the sugar leaving group and the highly sterically
hindered environment of the mechanical bond. Ultimately, by
treating rotaxanes 4 with amine 5, preactivated with AlMe3,25 and
heating the reaction mixture for 16 h, we achieved complete
consumption of the rotaxane starting materials to give
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Scheme 2. Substitution of the Chiral Glucose Unit To Give
a
Mechanically Planar Chiral Rotaxanes 6
1
Figure 5. Partial H NMR (600 MHz, CDCl3, 300 K), with selected
signals assigned, of (i) (Rmp)-6, (ii) their corresponding non-interlocked
thread, and (iii) (Smp)-6. See the Supporting Information for the
complete assignment. Labeling is as shown in Scheme 2. Residual
solvent signals are shown in gray.
a
b
3.8 equiv 5, 2.5 equiv AlMe3, PhMe, 80 °C, 16 h. Isolated yield after
column chromatography.
Our approach also allowed us to unambiguously assign the
absolute stereochemistry of the mechanical bond, which had also
not previously been achieved. Given the synthetic utility of the
active template method for the synthesis of rotaxanes,13,14 this
approach should prove general and, by avoiding the need for
CSP-HPLC, scalable. Thus, these proof-of-concept studies open
up this under-explored form of molecular asymmetry for study,
and we anticipate that this will lead to exciting developments
across a range of areas including materials, sensing, and catalysis.
Ultimately, by combining mechanical chirality with the well-
developed chemistry of rotaxane molecular shuttles, it may prove
possible to realize molecular machines that display dynamic
control over chiral space, such as switchable catalysts that can
produce either hand of a desired product in response to external
stimuli.28 Work toward these challenging objectives, as well as
development of diastereoselective active template coupling
reactions to deliver stereoselective chiral auxiliary methodologies
for the synthesis of mechanically chiral molecules,23 is underway.
Figure 4. (a) CSP-HPLC and (b) CD analysis of 6 and [6·Cu]·PF6.
mechanically planar chiral rotaxane 6 in 76% and 67% isolated
yield from (D,Rmp)-4 and (D,Smp)-4, respectively (Scheme 2).
The optical purities of rotaxanes 6 were confirmed by
analytical CSP-HPLC (Figure 4a). Pleasingly, reaction of
(D,Rmp)-4 gave rise to one enantiomer of rotaxane 6 in an er of
99.3:0.7, while reaction of (D,Smp)-4 gave the other as a single
stereoisomer (>99.5:<0.5). As substitution of the glucose unit
does not affect the relative orientation of the thread and
macrocycle, the configuration of the mechanical bond in
rotaxanes 6 can be assigned unambiguously. Thus, (D,Rmp)-4
and (D,Smp)-4 gives rise to rotaxanes (Smp)-6 and (Rmp)-6 in 98.6
and >99% ee, respectively.26 Inversion of the mechanical
stereochemical label is due to formal inversion of the A→B
axis as a result of substituting the glucose unit (Scheme 2).
The enantiomeric nature of rotaxanes 6 is apparent from their
CD spectra (Figure 4b), which are mirror images of one another.
Re-introducing CuI into the macrocyclic ligand gave samples
with more complex CD spectra in which the sign of the CD effect
inverts at λ = 266 and 295 nm. In both cases the amplitude of the
CD effect observed is relatively large.27 Furthermore, although
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
s.m.goldup@qmul.ac.uk
■
Notes
The authors declare no competing financial interest.
1
ACKNOWLEDGMENTS
the H NMR spectra of the enantiomers of rotaxane 6 are
■
identical, comparison with the corresponding achiral, thread
clearly demonstrates the chiral environment of the mechanical
bond (Figure 5): He and Hg, which are enantiotopic in the thread,
are diastereotopic in rotaxane 6, and both split into two widely
separated signals. The significant deshielding of Hf in rotaxanes 6
compared to the non-interlocked thread is tentatively assigned to
a hydrogen bond between the amide NH and the bipyridine unit,
as previously described.13e
CSP-HPLC methods for the analysis of rotaxanes 6 were
developed by Regis Technologies, Inc., and the authors are
grateful to Ted Szczerba and Jelena Kocergin for their help. The
authors thank Dan Pantoş of the University of Bath and John
Viles of QMUL for assistance with the CD measurements. High-
resolution mass spectroscopy was carried out by the EPSRC
National Mass Spectroscopy Service in Swansea. X-ray
crystallography was carried out at QMUL by Majid Motevalli.
The authors are grateful to Fluorochem for the gift of reagents.
This work was supported financially by the Royal Society and the
EPSRC. S.M.G. is a Royal Society Research Fellow.
In conclusion, we have succeeded for the first time in
synthesizing mechanically planar chiral rotaxanes in high
enantiopurity without the need for chiral separation techniques.
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(15) Substitution of stopper units in rotaxanes using reactions that do
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Stoddart and co-workers: (a) Rowan, S. J.; Stoddart, J. F. J. Am. Chem.
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A.; Leigh, D. A.; Mullen, K. M. Chem. Sci. 2011, 2, 1922.
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̈
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̈
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(23) We originally described the sugar unit as a chiral auxiliary.
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