Dynamic Control of Chiral Space Through Local Symmetry Breaking in a Rotaxane Organocatalyst

Article abstract of DOI:10.1002/anie.201908330

We report on a switchable rotaxane molecular shuttle that features a pseudo-meso 2,5-disubstituted pyrrolidine catalytic unit on the axle whose local symmetry is broken according to the position of a threaded benzylic amide macrocycle. The macrocycle can

Full text of DOI:10.1002/anie.201908330

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Accepted Article
Title: Dynamic Control of Chiral Space Through Local Symmetry
Breaking in a Rotaxane Organocatalyst
Authors: Marcel Dommaschk, Javier Echavarren, David Leigh, Vanesa
Marcos, and Thomas A Singleton
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908330
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10.1002/anie.201908330
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Dynamic Control of Chiral Space Through Local Symmetry
Breaking in a Rotaxane Organocatalyst
Marcel Dommaschk, Javier Echavarren, David A. Leigh,* Vanesa Marcos and Thomas A. Singleton
Abstract We report on a switchable rotaxane molecular shuttle that
features a pseudo-meso 2,5-disubstituted pyrrolidine catalytic unit on
the axle whose local symmetry is broken according to the position of
a threaded benzylic amide macrocycle. The macrocycle can be
selectively switched with high fidelity (with light in one direction; with
catalytic acid in the other) between binding sites located to either side
of the pyrrolidine unit. The position of the macrocycle dictates the
facial bias of the rotaxane-catalyzed conjugate addition of aldehydes
to vinyl sulfones. The pseudo-meso non-interlocked thread does not
afford significant selectivity as a catalyst (2-14 % ee), whereas the
rotaxane affords selectivities of up to 40 % ee with switching of the
position of the macrocycle changing the handedness of the product
formed (up to 60 % Dee).
binding site in E-1 and the glycyl amide group the preferred
binding site in Z-1.[22]
Compounds E- and Z-2 can be considered pseudo-meso[23]
structures due to the symmetrical local environment of the central
region of the axle (Figure 1a). In contrast, in rotaxanes E-1 and Z-
1 the macrocycle breaks the local symmetry of the pyrrolidine unit
in opposite senses according to its thermodynamically preferred
position on the axle (Figure 1b). Binding to the E-acyl hydrazone
locates the macrocycle close to the (R)-chiral center of the
pyrrolidine ring (Figure 1b); we term this form “enhanced-(R)” as
the macrocycle projects additional steric bulk and the potential for
other types of non-covalent interactions into the space around the
pyrrolidine nitrogen atom from the direction of the (R)-center.
Binding of the macrocycle to the glycyl amide (the preferred co-
conformer[24] in Z-1) changes the stereoelectronic environment in
a similar way but from the perspective of the opposite (S)-chiral
center (Figure 1b). As the binding co-conformations of benzylic
amide macrocycles with pyridyl-E-acyl hydrazones[22] and glycyl
amides[21b-d] are structurally quite similar, the enhanced-(R) and
enhanced-(S) co-conformers should provide environments
around the pyrrolidine nitrogen atom of fairly similar shape but of
opposite handedness. To break local symmetry in this way it is
unnecessary to restrict the macrocycle to different regions of the
thread with a kinetic barrier,[14] and the advantage in not doing so
is that it should be possible to dynamically switch between the
pseudo-enantiomeric enhanced-(R) and enhanced-(S) forms of
the rotaxane organocatalyst.
Whether or not an object has a superimposable mirror image is
formally a binary issue.[1] Often, however, it is the extent to which
chirality is expressed on the space surrounding a key region of a
molecular structure that is important for the effective transmission
of asymmetry.[2] Fledgling artificial molecular machines have been
developed[3] that can transfer sequence[4] and polydispersity[5]
information through to products, and that can be programmed to
stereoselectively deliver different outcomes[6] when promoting
successive chemical reactions. Enantiodivergent asymmetric
catalysis has been demonstrated with solvent-responsive helical
polymers,[7] redox-sensitive metal complexes[8] and overcrowded
alkene rotary motors[9].[10-12] The trapping of a macrocycle to one
side of a prochiral center with a steric barrier (a form of
)
atropisomerism[13] has previously been used[14] to break
symmetry[15] and induce mechanical point-chirality[16] in
rotaxanes. We reasoned that combining an extension of the latter
principle with the controllable change of macrocycle position
possible in stimuli-responsive molecular shuttles[17] could provide
a strategy for achieving dynamic control over the effective
“handedness” of the chiral space around a catalytic site on a
rotaxane axle.[18,19] This could, in principle, be used to switch the
enantioselectivity of the product formed from asymmetric
catalysis with a rotaxane-based molecular machine.
Rotaxane 1 and free thread 2 are shown in Figure 1. The
central region of the axle contains a 2,5-disubstituted pyrrolidine
unit (red) with a pyridyl-acyl hydrazone[20] (E- and Z- colored
purple and orange, respectively) to one side and a glycine amide
(green) to the other.[21] The pyridyl-acyl hydrazone and glycyl
amide groups are binding sites for the benzylic amide macrocycle
in rotaxane E/Z-1, with the pyridyl-acyl hydrazone the preferred
[*]
Dr. M. Dommaschk, J. Echavarren, Prof. D. A. Leigh, Dr. V. Marcos,
Dr. T. A. Singleton
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (UK)
E-mail: david.leigh@manchester.ac.uk
Homepage: http://www.catenane.net
Figure 1. Structures of (a) thread 2 and (b) rotaxane 1. The 2,5-substituted
pyrrolidine unit (red) of 2 is locally symmetric, with the symmetry only broken
four bond lengths in either direction from the pyrrolidine nitrogen atom, a
potential active site for organocatalysis. In rotaxane 1 the space around the
pyrrolidine nitrogen changes effective handedness according to the position of
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201908330
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the macrocycle: in E-1 the major co-conformer has the macrocycle
encapsulating the E-acyl hydrazone (purple) adjacent to the (R)-stereocenter
(“enhanced-(R)” pseudo-enantiomer); in Z-1 the major co-conformer has the
macrocycle encapsulating the glycine amide group (green) adjacent to the (S)-
stereocenter (“enhanced-(S)” pseudo-enantiomer). Conditions: E-1 to Z-1:
300 nm, 5 mW/cm2, CH2Cl2, 60 min, 95 %. Z-1 to E-1: 0.1 vol% CF3CO2H,
CH2Cl2, 30 min, then Et3N (0.2 vol%), quantitative.
lack of a chemical shift change in Hi confirms the macrocycle does
not circumscribe the glycyl unit.
In contrast, the significant upfield shifts of the Hi and Hh protons
in Z-1 with respect to Z-2 (DdHi = -0.5 and -0.9 ppm; DdHh = -0.75
and -1.31 ppm) indicate that the macrocycle is positioned over the
glycine amide unit in Z-1,[22] with small shifts in some of the pyridyl
acyl hydrazone protons again a result of close proximity to the
macrocycle. The chemical shifts changes are very similar to those
of a previous pyridyl-acyl hydrazone shuttle showing excellent
positional integrity in each rotaxane state.[22]
Having established that the macrocycle can be selectively
switched between the different sides of the pyrrolidine unit in
rotaxane 1, we investigated the effectiveness of the local
symmetry breaking in influencing the enantioselectivity of a
catalyzed reaction, namely the enamine-mediated conjugate
addition of aldehydes 3a-3c to a vinyl bis-sulfone 4 (Scheme 1).[25]
Thread E-2 and rotaxane E-1 were obtained in 8 and 9 steps,
respectively (see Supporting Information, Scheme S3). The key
rotaxane-forming reaction to form E-1, a five-component ‘clipping’
macrocyclization of isophthaloyl dichloride and p-xylylenediamine
around the pyridyl-acyl E-hydrazone template, proceeded in 57 %
yield.[22] The Z-acyl hydrazone isomers, Z-1 and Z-2, were each
formed in 95% yield by irradiation of the corresponding E-
rotaxane or thread with 300 nm UV-light (see Supporting
Information). The downfield shift of the hydrazone NH proton (He;
Dd ~2.0 ppm, Figure 2) caused by intramolecular hydrogen
bonding
is
characteristic of the
Z-acyl hydrazone
stereochemistry.[22] The reverse Z-to-E isomerization proceeded
quantitatively with a thermal half-life of ~4 min for both 1 and 2
when triggered with 0.1% v/v trifluoroacetic acid followed by
neutralization with Et3N (Scheme 1, Figure S7).
Scheme 1. Asymmetric catalysis of the enamine-mediated conjugate addition
of aldehydes 3a-c to vinyl sulfone 4. Reagents and conditions: (i) 3a-3c (0.1 M),
4 (0.05 M), E/Z-1 or E/Z-2 (5 mM), CDCl3 (0.4 mL), r.t., 1-8 h; (ii) EtOH (1 mL),
NaBH4 (excess), 0 °C, 30 min; (iii) UV light, 300 nm, 5 mW/cm2, 60 min; (iv)
Trifluoroacetic acid (0.1 vol%), then Et3N (0.2 vol%).
A loading of 10 mol% of rotaxane 1 or thread 2 proved sufficient
to achieve high conversions (94-97%) in 1-8 hours at room
temperature in chloroform (Supporting Information, Section S4).
The progress of the reactions was monitored by 1H NMR
spectroscopy (Figure S2). The resulting aldehydes were reduced
with NaBH4 to the corresponding alcohols (5a-c) in situ to avoid
racemization during work up, and separated by chiral HPLC.[25]
The results are shown in Table 1 (see Supporting information,
Figures S3-S5 and Tables S1-S3).
As anticipated, both the E- and Z-stereoisomers of the pseudo-
meso thread 2 gave poor enantioselectivities in the catalyzed
reactions. Enantiomeric excesses (ee’s) of 2-6% were generated
using E-2 (Table 1, entries 3, 7 and 11) and 6-14% with Z-2 (Table
1, entries 4, 8 and 12). In each case the small ee’s produced by
E-2 and Z-2 were in favor of the same product enantiomer.
The corresponding rotaxanes show significant improvement in
their performance as asymmetric catalysts.[18g] The presence of
the macrocycle on the axle increases the ee from 2-6% using
pseudo-meso E-2 to 24-40% using enhanced-(R) rotaxane
catalyst E-1 (Table 1, entries 1, 5 and 9). The position of the
macrocycle breaks the pseudo-symmetry of the pyrrolidine unit,
effectively projecting out from the (R)-stereocenter into the space
around the pyrrolidine nitrogen atom. Rotaxane Z-1 shows more
modest increases in ee’s: from 6-14% with Z-2 to 16-20% using
Z-1 (Table 1, entries 2, 6 and 10). Significantly, however, in every
Figure 2. Partial 1H NMR spectra (600 MHz, CDCl3, 298 K) of (i) thread E-2;
(ii) rotaxane E-1; (iii) rotaxane Z-1 obtained by irradiation of E-1 (300 nm,
5 mW/cm2, CH2Cl2, 60 min); (iv) thread Z-2 obtained by irradiation of E-2
(300 nm, 5 mW/cm2, CH2Cl2, 60 min). The lettering and color assignments
correspond to those shown in Figure 1.
The position of the macrocycle on the axle of the rotaxanes was
determined by 1H NMR spectroscopy. Both hydrazone
stereoisomers of the free thread, E-2 and Z-2, are ~1:1 mixtures
of rotamers due to slow rotation of the acyl hydrazone OC-NH
bond (Figure 2 i and iv and Scheme S1). However, rotaxane E-1
exists predominantly as a single rotamer (Figure 2 ii) as only one
hydrazone configuration maximizes the number of strong
intercomponent hydrogen bonds. The upfield shift of the pyridine
and CH hydrazone protons (Ha-Hd, Dd = -0.2 to -1.0 ppm) together
with pyrrolidine proton Hf (Dd
= -0.8 ppm) confirm the
encapsulation of the pyridyl E-acyl hydrazone by the macrocycle.
Modest upfield shifts in the Hh protons result from their proximity
in space to an aromatic ring of the macrocycle (Figure S9). The
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case the Z-form of the rotaxane favors the formation of the
opposite enantiomer to that favored by the E- rotaxane: switching
the position of the macrocycle from one side of the pyrrolidine unit
to the other reverses the enantioselectivity of the catalyst. The
greatest difference in enantioselectivities occurs with hexanal
(3b) as the substrate, with switching the rotaxane catalyst from
the enhanced-(R) to the enhanced-(S) form (i.e. E-1 to Z-1)
resulting in Dee of 60% for the product alcohol 5b (Table 1, entries
5 and 6). The lower ee’s generated by the Z-rotaxane are likely a
reflection of the pseudo-meso threads E- and Z-2 both favoring
the formation of the same product enantiomers as E-1. Similar but
less pronounced switching of ee is observed by iminium activation
(Section S4.2).
(20-40 % ee for each handedness of product 5b; cf. 50-54 % ee
with the first overcrowded-alkene rotary catalysts[9a]).
Nevertheless, the strategy was shown to (i) enhance the effective
asymmetry,[18g] and (ii) switch the apparent handedness, of the
environment around a catalytic site in a rotaxane-based molecular
shuttle. A particular advantage of the concept is that it should be
broadly applicable to other rotaxane systems, including designs
featuring more than one ring and catalytic center or axles with a
pseudo-prochiral
center
rather
than
pseudo-meso
stereochemistry. Strategies that combine chemical, geometrical
and dynamic design elements are likely to become increasingly
important in the spatio-temporal control of chemical
transformations with compound molecular machines.[26]
Table 1. Enamine-mediated conjugate addition of aldehydes 3a-c to vinyl
sulfone 4 using catalysts 1 and 2.
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council (EPSRC; EP/P027067/1) and the EU (European
Research Council (ERC) Advanced Grant no. 786630; H2020
project Euro-Sequences, H2020-MSCA-ITN-2014, Grant no.
642083) for funding and the University of Manchester Mass
Spectrometry Service Centre for high-resolution mass
spectrometry. D.A.L. is a Royal Society Research Professor.
Entry[a]
1
Aldehyde
Catalyst
ee of 5[b]
(R) 38
E-1
Z-1
E-2
Z-2
E-1
Z-1
E-2
Z-2
E-1
Z-1
E-2
Z-2
Keywords: molecular machines • rotaxanes • switchable
2
3
(S) 18
(R) 2
catalysts • chirality • asymmetric catalysis
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(S) 40
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(S) 14
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10.1002/anie.201908330
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Changing hands. Leigh et al use the
stimuli-induced change of macrocycle
position in a rotaxane to switch the
effective handedness of a catalytic
center on the axle. The dynamic
switching is used to reverse the
enantioselectivity of an enamine-
mediated conjugate addition.
M. Dommaschk, J. Echavarren, D. A.
Leigh,* V. Marcos, T. A. Singleton
Page No. – Page No.
Dynamic Control of Chiral Space
Through Local Symmetry Breaking in
a Rotaxane Organocatalyst
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