Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis

Article abstract of DOI:10.1016/j.chempr.2020.02.006

Rotaxanes are interlocked molecules in which a molecular ring is trapped on a dumbbell-shaped axle because of its inability to escape over the bulky end groups, resulting in a so-called mechanical bond. Interlocked molecules have mainly been studied as components of molecular machines, but the crowded, flexible environment created by threading one molecule through another has also been explored in catalysis and sensing. However, so far, the applications of one of the most intriguing properties of interlocked molecules, their ability to display stereogenic units that do not rely on the stereochemistry of their covalent subunits, termed “mechanical chirality,” have yet to be properly explored, and prototypical demonstration of the applications of mechanically chiral rotaxanes remain scarce. Here, we describe a mechanically planar chiral rotaxane-based Au complex that mediates a cyclopropanation reaction with stereoselectivities that are comparable with the best conventional covalent catalyst reported for this reaction. Molecules that exist in non-identical mirror image forms are referred to as chiral. Chirality can arise because of various molecular features in which atoms are held in fixed orientations that are themselves chiral, and typically such “stereogenic units” are maintained by direct bonds between atoms. Molecular chirality can also arise by threading a dumbbell-shaped molecule through a molecular ring to generate a rotaxane. However, these molecules have not been investigated significantly because until recently they were extremely hard to make in one mirror image form. Here, we report the first example of a catalyst based on such a “mechanically chiral” rotaxane. Catalysis with chiral molecules is extremely important in modern chemistry because it is one of the most efficient ways to make chiral molecules for applications in healthcare and other areas. Our results demonstrate that mechanically chiral molecules are a promising and underexplored platform for generating such catalysts. We report an enantioselective catalyst based on a “mechanically chiral” rotaxane. Catalysis with chiral molecules is extremely important in modern chemistry because it is one of the most efficient ways to make chiral molecules for applications in many areas. Our results demonstrate, for the first time, that mechanically chiral molecules are a promising and underexplored platform for generating such catalysts. We achieve enantioselectivities for the Au^I-catalyzed Ohe-Uemura cyclopropanation of benzoate esters comparable to previously reported covalent catalysts.

Full text of DOI:10.1016/j.chempr.2020.02.006

Article
Synthesis of a Mechanically Planar Chiral
Rotaxane Ligand for Enantioselective Catalysis
Andrew W. Heard, Stephen M.
Goldup
s.goldup@soton.ac.uk
HIGHLIGHTS
We synthesized a mechanically
planar chiral rotaxane for
catalytically active gold ions
We demonstrate enantioselective
catalysis with a mechanically
planar chiral rotaxane
Our results suggest that
mechanical stereochemistry has
untapped potential in
enantioselective catalysis
We report an enantioselective catalyst based on a ‘‘mechanically chiral’’ rotaxane.
Catalysis with chiral molecules is extremely important in modern chemistry
because it is one of the most efficient ways to make chiral molecules for
applications in many areas. Our results demonstrate, for the first time, that
mechanically chiral molecules are a promising and underexplored platform for
generating such catalysts. We achieve enantioselectivities for the AuI-catalyzed
Ohe-Uemura cyclopropanation of benzoate esters comparable to previously
reported covalent catalysts.
Heard & Goldup, Chem 6, 1–13
April 9, 2020 ª 2020 The Author(s). Published by
Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.02.006

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Article
Synthesis of a Mechanically Planar
Chiral Rotaxane Ligand
for Enantioselective Catalysis
Andrew W. Heard1 and Stephen M. Goldup1,2,
*
SUMMARY
The Bigger Picture
Molecules that exist in non-
identical mirror image forms are
referred to as chiral. Chirality can
arise because of various molecular
features in which atoms are held in
fixed orientations that are
Rotaxanes are interlocked molecules in which a molecular ring is trapped on a
dumbbell-shaped axle because of its inability to escape over the bulky end
groups, resulting in a so-called mechanical bond. Interlocked molecules have
mainly been studied as components of molecular machines, but the crowded,
flexible environment created by threading one molecule through another has
also been explored in catalysis and sensing. However, so far, the applications
of one of the most intriguing properties of interlocked molecules, their ability
to display stereogenic units that do not rely on the stereochemistry of their co-
valent subunits, termed ‘‘mechanical chirality,’’ have yet to be properly
explored, and prototypical demonstration of the applications of mechanically
chiral rotaxanes remain scarce. Here, we describe a mechanically planar chiral
rotaxane-based Au complex that mediates a cyclopropanation reaction with
stereoselectivities that are comparable with the best conventional covalent
catalyst reported for this reaction.
themselves chiral, and typically
such ‘‘stereogenic units’’ are
maintained by direct bonds
between atoms. Molecular
chirality can also arise by
threading a dumbbell-shaped
molecule through a molecular ring
to generate a rotaxane. However,
these molecules have not been
investigated significantly because
until recently they were extremely
hard to make in one mirror image
form. Here, we report the first
example of a catalyst based on
such a ‘‘mechanically chiral’’
rotaxane. Catalysis with chiral
molecules is extremely important
in modern chemistry because it is
one of the most efficient ways to
make chiral molecules for
INTRODUCTION
Interlocked molecules such as rotaxanes, in which a dumbbell-shaped axle is
threaded through a macrocycle, and catenanes, in which two or more macrocycles
are held together in a manner akin to links in a chain,1 are most commonly investi-
gated as components of molecular machines,2 building on the pioneering work of
Stoddart and Sauvage, who were awarded the Nobel Prize for their efforts in
2016.3–5 In contrast, one of the most intriguing structural properties of interlocked
molecules, their ability to display enantiotopic stereogenic elements that do not
rely on covalent stereochemistry,6 has received much less attention, despite the pos-
sibility of such enantiomerism being discussed early in the development of the
field.7,8 Such ‘‘mechanical’’ stereogenic units can arise because of desymmetrization
of one of the covalent subunits by the relative position of the other (co-conforma-
tional chirality), the combination of subunits with appropriate symmetry properties
(conditional mechanical chirality), or the unconditional topology of the mechanical
bond itself (Figure 1A).6,9,10
applications in healthcare and
other areas. Our results
demonstrate that mechanically
chiral molecules are a promising
and underexplored platform for
generating such catalysts.
The relative paucity of even prototypical applications of mechanically chiral mole-
cules is at least in part because enantiopure samples were historically hard to
synthesize, with the pioneering work carried out by Vogtle, Okamoto, and Sauv-
¨
age,15,16 requiring the use of chiral stationary phase high-performance liquid chro-
matography (HPLC) to separate the enantiomeric products from a racemic mixture.
Using this approach, Vogtle and co-workers showed that mechanically planar chiral
rotaxanes and topologically chiral catenanes displayed strong electronic circular
Chem 6, 1–13, April 9, 2020 ª 2020 The Author(s). Published by Elsevier Inc.
1
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Figure 1. Different Forms of Chirality in Mechanically and Covalently Bonded Molecules
(A) Examples of (i) co-conformational, (ii) conditional mechanical, and (iii) unconditional
topological stereogenic units.
(B) Examples of covalently bonded chiral acyl transfer catalysts based on (i) point,11 (ii) axial,12 (iii)
planar,13 and (iv) helical14 stereogenic units.
dichroism (CD),15 Hirose and co-workers disclosed a mechanically planar chiral
rotaxane that selectively binds and senses the enantiomers of small chiral mole-
cules,17 and Takata and co-workers demonstrated that the mechanically planar chi-
ral stereogenic unit can direct the helical twist of a poly-diacetylene material.18
More recently, Saito and co-workers demonstrated the separation of co-conforma-
tionally mechanically planar chiral rotaxanes and used the link between the rate of
racemization and co-conformational motion to determine the energy barrier for
shuttling19 and Credi and co-workers demonstrated a co-conformationally me-
chanically planar chiral molecule that shuttles between achiral and chiral states,
the latter of which could be biased by the binding of a small chiral guest.20
However, of these unusual forms of stereochemistry, only co-conformational point
chirality has been exploited in catalysis; in 2015, Leigh and co-workers demon-
strated an enantioselective co-conformationally covalent point chiral organocata-
lyst (Figure 1Ai) that mediated enamine and iminium activation.21,22 (The same
authors have developed molecular ratchets and motors based on this stereogenic
element.23,24) In contrast, the full complement of covalent stereogenic units,25
including point,11 axial,12 planar,13 and helical14 chirotopic elements26 have
been applied in the development of new scaffolds to mediate enantioselective
processes (Figure 1B) since the Nobel Prize was awarded in 2001 to Noyori,
Knowles, and Sharpless for their contributions to the development of enantioselec-
tive catalysis.27–29 Indeed, recent work has aimed at expanding the mechanisms
by which stereochemical information is transferred to the reaction space
including the use of chiral counterions,30 chiral-at-metal systems,31 helical artifi-
cial32 and natural33,34 polymers, chiral solvents,35 chiral capsules,36 and other
confined environments.37
Building on our recent effort to improve access to mechanically chiral molecules
through the use of chiral derivatizing units38,39 and auxiliaries,40 here we demon-
strate the first example of enantioselective catalysis with a mechanically planar
chiral rotaxane, one of the simplest conditional mechanical stereogenic units,
which arises when an achiral macrocycle with Cnh point group symmetry encircles
an achiral axle with Cnv point group symmetry.6,9,10 Our rotaxane catalyst, whose
1School of Chemistry, University of Southampton,
Highfield, Southampton SO17 1BJ, UK
structure was not designed or optimized, displays enantioselectivities in an
AuI-mediated cyclopropanation reaction comparable to the best reported covalent
2Lead Contact
catalyst.41 Our results suggest that mechanical stereochemistry has untapped
*Correspondence: s.goldup@soton.ac.uk
https://doi.org/10.1016/j.chempr.2020.02.006
potential in the development of new enantioselective catalytic systems.
2
Chem 6, 1–13, April 9, 2020

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Scheme 1. Synthesis of Mechanically Planar Chiral Rotaxane Precatalysts
Reagents and conditions: (1) (i) [Cu(MeCN)4]PF6, 1H-sponge, CH2Cl2, room temperature (RT), 8 h;
(ii) KCN, MeOH-CH2Cl2 (1:1), RT, 30 min; (iii) H2O2 (35% w/w in H2O), CH2Cl2, RT, 5 min. 72%
combined yield over 3 steps prior to separation of diastereomers. (S,Rmp)-4: 30%, 98% ee, >99:
<1 dr; (S,Smp)-4: 24%, (S,Smp)-4-(R,Smp)-4-(S,Rmp)-4 = 98.4:1.0:0.6. (2) LiHMDS, tetrahydrofuran,
ꢀ78ꢁC then, BnI, ꢀ78ꢁC to RT, 18 h. (Rmp)-5: 81% (98% ee). (Smp)-5 63% (98% ee; data not shown, see
Supplemental Information). (3) HSiCl3, NEt3, PhMe, CH2Cl2, 100ꢁC, 3 days. (4) (Me2S)AuCl, CH2Cl2,
RT, 1 h. (Rmp)-5: 64% yield over two steps (98% ee). (Smp)-6: 62% (98% ee; data not shown, see
Supplemental Information).
RESULTS AND DISCUSSION
Synthesis and Characterization of Mechanically Planar Chiral Complex
[Au(6)(Cl)]
To demonstrate the potential of mechanical stereochemistry in catalysis, we
selected a AuI-mediated reaction for our study. AuI-mediated reactions are inher-
ently difficult to render enantioselective as a result of the linear coordination chem-
istry of the metal ion.42 These challenges are typically overcome through the use of
large, monodentate ligands that project substituents into the reaction space or di-
AuI complexes, in which aurophilic interactions pre-organize the complex with one
metal ion playing the role of the catalyst and the other of a structural unit,42,43
although employing secondary interactions in bifunctional catalysts is a promising
emerging strategy.44–46 Given that we have previously shown that the mechanical
bond can be used to project steric bulk around an AuI center, leading to highly dia-
stereoselective catalysis,47 we proposed that similar effects might be observed in
the case of a mechanically chiral derivative, leading to enantioselective catalysis.
Rotaxane AuI complex [Au(6)(Cl)] was synthesized using our small macrocycle modifica-
tion48 of Leigh’s active template49 Cu-mediated alkyne-azide cycloaddition reaction
(AT-CuAAC),50,51 employing amino-acid-derived azide 1 as a stereo-differentiating
unit,39 borane-protected propargylic phosphine 2 as the alkyne coupling partner, and
readily availableC1h (Cs) symmetric macrocycle 3,52 as the key mechanical bond forming
step. We typically carry out the AT-CuAAC reaction in the presence of excess NiPr2Et,
which accelerates the reaction by favoring the formation of the key macrocycle-CuI-ace-
tylide complex intermediate. However, in this case, NiPr2Et was found to cause epime-
rization of the azide stereocenter, resulting in a mixture of all four possible stereoiso-
meric products. Replacing NiPr2Et with Proton Sponge drastically reduced the
epimerization side reaction, allowing the mixture of diastereomeric phosphine oxides
4 to be separated53 with excellent stereochemical purity after demetallation and oxida-
tive work-up. Using this sequence, we were able to isolate rotaxanes (S,Rmp)-4 (98%
ee, >99: <1 dr) and (S,Smp)-4 ((S,Smp)-4-(R,Smp)-4-(S,Rmp)-4 = 98.4:1.0:0.6, i.e., >98%
Chem 6, 1–13, April 9, 2020
3

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Figure 2. Characterization of Rotaxanes 4 and 5
(A) Solid-state structure of (S,Rmp)-4 with selected intercomponent interactions highlighted (atom
˚
labels and colors [O, dark gray; N, dark blue] as in Scheme 1, selected distances [A]: HgdddO = 2.4,
Hgdddcentroid = 2.6, HhdddN = 2.5, Hjdddcentroid = 3.2, and HEdddO = 2.5).
(B) Solid-state structure of (S,Smp)-4 with selected intercomponent interactions (atom labels and
˚
colors [O, dark gray; N, dark blue] as in Scheme 1, selected distances [A]: HhdddN = 2.4,
HidddC = 2.6, HjdddN = 2.7, and HEdddO = 2.7). It should be noted that the asymmetric unit
contains an oxidized derivative of (S,Smp)-4 as a disordered impurity.54 The figure depicts the
component of the unit cell that is unaffected by this disorder.
(C) Partial 1H NMR (CDCl3, 400 MHz, 298 K) of (i) macrocycle 3, (ii) rotaxane (S,Rmp)-4, (iii) rotaxane
(S,Smp)-4, and (iv) rotaxane (Rmp)-5. Selected signals are assigned and color coded (see Scheme 1
for labels; Hk and Ho, assigned arbitrarily, are the ortho protons of the diastereotopic axle benzyl
groups). Signals corresponding to macrocycle 3 are all shown in blue for clarity.
ee in the mechanical stereogenic unit) in an acceptable combined yield of 54%. Alkyl-
ation of diastereomer (S,Rmp)-4 withBnIerased thecovalentstereogenic unitto produce
rotaxane (Rmp)-5, in which the mechanical bond provides the sole stereogenic unit in
excellent yield and enantiopurity (81% and 98% ee). Subsequent reduction of the phos-
phine oxide moiety and coordination of AuCl produced the AuI precatalyst [Au((Rmp)ꢀ
6)(Cl)], theenantiopurityof which wasassumed to be the same as that of (Rmp)-5 (98%ee)
as the mechanical bond is configurationally stable. The same procedures starting from
(S,Smp)-4 produced [Au((Smp)ꢀ6)(Cl)] (98% ee).
Rotaxanes 4, 5, and [Au(6)(Cl)] were isolated and characterized in full by NMR, mass
spectrometry (MS), HPLC (4 and 5), and CD (see Supplemental Information for full de-
tails). The absolute stereochemistries of phosphine oxides (S,Rmp)-4 and (S,Smp)-454
were assigned by single-crystal X-ray diffraction (SC-XRD)55 (Figures 2A and 2B); the
internal stereochemical reference provided by the azide-derived unit allowed the
4
Chem 6, 1–13, April 9, 2020

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
orientation of the macrocycle to be determined unambiguously and the stereochemical
labels were assigned using our established approach (see Supplemental Information
for details).6,9,10 The absolute stereochemistry of rotaxanes 5 and [Au(6)(Cl)] were in-
ferred by noting that the mechanical stereochemistry of the corresponding diastereo-
meric starting materials cannot be altered in subsequent reactions.
The 1H NMR spectra of diastereomers (S,Rmp)-4 and (S,Smp)-4 (Figures 2Cii and 2Ciii,
respectively) display the typical features of such interlocked molecules;48 many of
the signals corresponding to the axle and macrocycle components, including HD,
HE, HM, and HN are shielded relative to the non-interlocked macrocycle (Figure 2Ci),
and triazole proton Hh appears at a high chemical shift due to the formation of an
intercomponent C–HdddN hydrogen bond with the bipyridine, as observed in the
solid-state structures (Figures 2A and 2B). However, their 1H NMR spectra are clearly
distinct, in keeping with the diastereomeric relationship between the two products,
as are their CD spectra (see Supplemental Information). Alkylation of rotaxanes 4 to
give rotaxanes 5, produced materials with identical 1H NMR spectra (Figure 2Biv) but
mirror image CD spectra (Figure 2D), in keeping with the enantiomeric relationship
between these products. Strikingly, in addition to the expected shielding/deshield-
ing of signals, the aromatic protons corresponding to the diastereotopic benzylic
units of the axle in rotaxanes 5 are clearly distinct (e.g., benzylic ortho protons Hk
and Ho), suggesting that the stereochemistry of the mechanical bond is well ex-
pressed onto the axle.
Enantioselective Cyclopropanation Reactions Mediated by Rotaxane
[Au((Rmp)ꢀ6)(Cl)]
With the precatalyst [Au((Rmp)ꢀ6)(Cl)] in hand, we investigated its behavior in the
enantioselective AuI-mediated variant of the Ohe-Uemura56 cyclopropanation of
alkenes by propargylic esters originally reported by Toste and co-workers using
(R)-DTBM-SEGPHOS(AuCl)2 and resulting in stereoselectivities from 60% to 94%
ee.41 More recently, Fuerstner and co-workers reported a mono-dentate 1,1-bi-2-
naphthol-derived phosphoramite ligand for the same reaction,57 and Toste and
co-workers reported a reaction system that employs Au nanoclusters embedded
in a chiral self-assembled monolayer.58
Under conditions previously optimized for an analogous achiral rotaxane-based
catalyst,47 [Au((Rmp)ꢀ6)(Cl)] mediated the reaction of benzoyl ester 7 with styrene
(8) to produce cyclopropanes 9 in excellent selectivity for the cis diastereomer
(Table 1, entry 1). The role of the CuI additive is to bind to the bipyridine moiety, pre-
venting the Lewis base inhibition of the AuI center; reactions in the absence of CuI
were unsuccessful (entry 2).47 Other cationic additives failed to activate the catalyst
(see Supplemental Information). Analysis of the purified major diastereomer by
chiral stationary phase HPLC revealed reasonable enantioselectivity for (1S,2R)-9
(er = 72:28).59 As expected, replacing [Au((Rmp)ꢀ6)(Cl)] with [Au((Smp)ꢀ6)(Cl)] pro-
duced 9 with opposite enantioselectivity (entry 3). Variation of the solvent led to
changes in the observed er of cis-9 but no significant improvement (entries 4–7).
Cooling the reaction to 0ꢁC improved the er of the major diastereomer to 79:21 (en-
try 8). Cooling the reaction mixture further led to no significant improvement and
slowed the process considerably (entry 9). For comparison, the same reaction medi-
ated by (R)-DTBM-SEGPHOS(AuCl)2 reported by Toste and co-workers produces cy-
clopropanes 9 in moderately higher and opposite stereoselectivity (entry 10).
With suitable conditions in hand (Table 1, entry 8), we performed a brief investigation of
the effect of substrate on the stereoselectivity of reactions mediated by [Au((Rmp)ꢀ6)(Cl)]
Chem 6, 1–13, April 9, 2020
5

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Table 1. Optimization of an Enantioselective Cyclopropanation Reaction Mediated by
[Au(6)(Cl)]a
c
c
Entrya
Solvent
CDCl3
CDCl3
CDCl3
MeNO2
CD2Cl2
CCl4
Temperature (ꢁC)
Time (h)
cis:transb
95:5
ercis
ertrans
58:42
–
1
25
25
25
25
25
25
25
0
1
72:28
–
2d
3e
4
1
n.r.
1
95:5
29:71
53:47
64:36
71:29
69:31
79:21
79:21
16:84
42:58
65:35
66:34
58:42
56:44
62:38
61:39
–
1
87:13
83:17
86:14
85:15
94:6
5
1
6
1
7
PhMe
1
8f
CDCl3
CDCl3
MeNO2
6
9
ꢀ35
25
24
0.5
96:4
10g
>20:<1
a[Au(6)(Cl)] with 84% ee was used for screening experiments unless otherwise stated.
bDetermined by 1H NMR analysis of the crude reaction product using C2Cl4H2 as an internal standard
(yield determination).
cDetermined by HPLC.
dReaction was conducted without the CuI additive.
eReaction conducted with [Au((Smp)ꢀ6)(Cl)].
fReaction conducted with [Au(6)(Cl)] with er = 99:1 stereopurity.
gReaction outcome reported by Toste and co-workers for (R)-DTBM-SEGPHOS(AuCl)2.41
(Figure 3). Variation of the styrene component in the reaction of benzoate ester 7 gave
cyclopropanes 10 and 11 in similar ee and de to 9, although the yield of the reaction was
much lower in the case of 2-Me-substituted product 11. Replacing styrene with allyl ben-
zene gave cyclopropane 12 in reasonable enantioselectivity but lower diastereoselectiv-
ity, as has previously been observed for aliphatic alkenes.41 Conversely, variation of the
propargylic ester component had a significant effect on the reaction stereoselectivity.
Whereas (R)-DTBM-SEGPHOS(AuCl)2 is reported to deliver higher stereoselectivity
with the pivaloyl derivative of propargyl ester 7, in the case of [Au((Rmp)ꢀ6)(Cl)], cyclopro-
pane 13 was produced with almost no enantioselectivity. Pleasingly, phenylacetate
ester-derived cyclopropane 14 was produced in comparable selectivity to 9, confirming
that a-alkyl esters are tolerated by [Au(6)(Cl)] and suggesting that the steric bulk of the
pivolyl moiety is responsible for the loss of stereoselectivity in the case of 13. Variation
of the benzoyl moiety to introduce strongly electron-withdrawing or -donating groups
(cyclopropanes 15 and 16, respectively) led to a reduction in reaction enantioselectivity.
In contrast, bulky alkyl groups on the benzoate moiety increased the reaction ee; p-tBu
benzoyl cyclopropane 17 and 3,5-di-tBu-substituted cyclopropane 18 were produced in
good yield and enantioselectivity. Cyclopropanes 9–18 were isolated by flash chroma-
tography prior to HPLC analysis; the catalyst and any associated decomposition prod-
ucts were readily removed from the product mixture.
6
Chem 6, 1–13, April 9, 2020

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Figure 3. Cyclopropane Products Synthesized Using [Au((Rmp)ꢀ6)(Cl)]
All reactions carried out under the conditions shown in Table 1, entry 8. Combined yields of
cyclopropanes and de were determined by 1H NMR analysis of the crude reaction product using
C2Cl4H2 as an internal standard. ee of the major cis diastereomer determined by HPLC analysis of
purified samples.59
Modeling of the AuI-Mediated Cyclopropanation of Styrene
Detailed modeling of interlocked molecules is challenging, given both their size and
flexibility. Previously, the catalytic behavior of an interlocked catenane organocata-
lyst was studied computationally by considering the catalytic fragment alone on the
assumption that the rest of the structure did not play a direct role in the reaction.60 In
the case of [Au(6)(Cl)], this clearly would not be a reasonable assumption as the me-
chanical bond is the sole source of stereochemistry. Also, the implied difference in
activation barrier, even for the most selective example reported above (18) is only
ꢂ4.5 kJmolꢀ1, a relatively small value for such a complex system where multiple con-
formations of the catalyst may be mechanistically relevant. These caveats notwith-
standing, in order to gain some qualitative insight into how interactions between
the reacting substrates and the rotaxane structure might influence the stereoselec-
tivity of the reaction, we conducted preliminary computational modeling of the re-
action of propargylic ester 7 and styrene (8) mediated by [Au(Rmp-6)(Cl)].
In brief (for full details see Supplemental Information), we began by locating the
lowest energy transition state (CAM-B3LYP/6-31G*/SDD(Au)) for the reaction of 7
with 8 mediated by [Au(PPh3)(Cl)], building on previous work by Echavarren and
co-workers.61 In keeping with this previous report, the reaction of the carbene
derived from 7 with 8 was found to be a two-step process. We thus assumed a similar
pathway for the reaction mediated by [Au(6)(Cl)] (Figure 4A); coordination of CuI and
abstraction of the Cl ligand gives rise to the proposed active catalyst [AuCu(6)]2+
,
which coordinates to alkyne 7 to give complex I that undergoes a rearrangement
to produce key carbene intermediate II. Addition of styrene to II produces carboca-
tion III via key transition state TSI, in the process setting the stereochemistry of C1 of
the cyclopropane product. Subsequent rapid ring closure gives rise to cyclopropane
9 and regenerates the catalyst.
In order to investigate the reaction mediated by rotaxane [Au(6)(Cl)], the transition
state model found for the reaction mediated by [Au(PPh3)(Cl)] was modified by
attachment to the CuI-coordinated metallorotaxane.62–64 A conformational search
(Spartan ’10, MMF)65 with the transition state fragment frozen yielded low-energy
conformers for each diastereomeric complex, which were optimized using density
functional theory (DFT) (Gaussian ‘09,66 CAM-B3LYP, 6–31G/SDD(Cu,Au)), again
with the transition state fragment frozen, to identify the lowest energy conformation.
Transition state optimization, first using an ONIOM method (CAM-B3LYP:UFF,
Chem 6, 1–13, April 9, 2020
7

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Figure 4. Reaction Pathway and Modeled Transition State Structures
(A) Reaction pathway presumed for the reaction of [Au(6)(Cl)] based on molecular modeling
(Gaussian ‘09, CAM-B3LYP, 6-31G*/SDD(Au)) of the reaction of 7 and 8 mediated by [Au(PPh3)(Cl)].
R = C(Bn)2CO2iPr.
(B) Modeled (CHCl3, CAM-B3LYP, 6-31G/SDD) structure of TS1 leading to (1R,2S)-9 for the reaction
of 7 with 8 mediated by [AuCu((Rmp)-6)]2+ in (i) sticks representation and (ii) close-up of the
8
Chem 6, 1–13, April 9, 2020

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Figure 4. Continued
transition state fragment in mixed space-filling and sticks representation. Selected
intercomponent interactions and the carbene-styrene interaction associated with the reaction
coordinate are highlighted in yellow and red, respectively.
(C) Modeled (CHCl3, CAM-B3LYP, 6-31G/SDD) structure of TS1 leading to (1S,2R)-9 for the reaction
of 7 with 8 mediated by [AuCu((Rmp)-6)]2+ in (i) sticks representation and (ii) close-up of the
transition state fragment in mixed space-filling and sticks representation. Selected
intercomponent interactions and the carbene-styrene interaction associated with the reaction
coordinate are highlighted in yellow and red, respectively.
6–31G/SDD(Au)), followed by
a full DFT optimization (CAM-B3LYP, 631G/
SDD(Cu,Au)) first in the gas phase then in solvent (CHCl3, polarizable continuum
model) yielded transition state models (Rmp,Re)-TS1 and (Rmp,Si)-TS1 (Figures 4B
and 4C, respectively) that were determined to be first order saddle points with a sin-
gle imaginary frequency.
Examining the models of (Rmp,Re)-TS1 and (Rmp,Si)-TS1 (Figures 4B and 4C, respec-
tively) reveals that, in spite of their size and large number of rotatable bonds, the
modeled catalyst structure is actually relatively rigid because of steric crowding com-
bined with the coordination of the CuI ion. A complex network of short intra- and in-
tercomponent contacts including CH hydrogen bonds, CH-p interactions, and
cation-p interaction between the CuI ion and one of the Ph rings of the phosphine
ligand are predicted to stabilize the system further and project the AuI center bearing
the reactive carbene moiety toward the macrocycle, into the space around one of the
phenoxy ether moieties. It is perhaps noteworthy that the optimized structures are
similar to the solid-state structures of rotaxanes 4 determined by X-ray diffraction
in which the phosphine substituent (O) is also projected toward the same aryl ether
moiety. Crowding around the AuI carbene moiety due to the mechanical bond is
clearly seen in the space-filling models of (Rmp,Re)-TS1 and (Rmp,Si)-TS1 (Figures
4Bii and 4Cii, respectively); the macrocycle provides a sterically crowded environ-
ment that shields one face of the carbene unit and restricts the rotation of the sub-
strate around the Au-P axis. The substrates are stabilized in the rotaxane environment
through a number of non-covalent interactions, in particular a C(carbene)H–O inter-
action in both structures and a CH-C(carbene) interaction in the case of (Rmp,Si)-TS1.
Thus, the modeling suggests that a mechanically bonded structure provides a well-
expressed chiral environment for the catalysis to take place within, which is consistent
with the reasonable enantioselectivities achieved experimentally.
Finally, comparison of the calculated relative energies of (Rmp,Re)-TS1 and (Rmp,Si)-
TS1 revealed remarkable agreement, given the size of the system, between
experiment and theory; (Rmp,Si)-TS1 was found to be favored by ꢂ2.3 kJmolꢀ1, cor-
responding to a stereoselectivity of 74:26 in favor of the major observed product
(1S,2R)-9. However, caution should be taken when interpreting this level of agree-
ment; modeling in the gas phase (6–31G/SDD) predicted the opposite stereoselec-
tivity ((Rmp,Re)-TS1 favored by ꢂ1.7 kJmolꢀ1). Conversely, re-optimization of TS1
with the larger 6–31G* basis set in the gas phase or in CHCl3 (single point calcula-
tion)67 resulted in a predicted selectivity for the correct diastereomer that exceeds
what is observed experimentally, demonstrating the uncertainty in the absolute
values generated in such complex systems. Furthermore, although extending the
modeling to the reactions leading to cyclopropanes 15 and 16 revealed reasonable
agreement with experiment, the same calculations for the reaction leading to cyclo-
propanes 13 predicted a high selectivity, in contrast to the low selectivity observed
experimentally (see Supplemental Information for details).
Chem 6, 1–13, April 9, 2020
9

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
Thus, the molecular models of (Rmp,Re)-TS1 and (Rmp,Si)-TS1 should be considered
qualitative, providing some insight into the potential interactions and a pictorial rep-
resentation of the chiral environment created by the mechanical bond around the re-
acting AuI carbene. A more detailed study, combined with many more comparisons
between experiment and theory, would be required to determine the details of the
key intermolecular interactions that lead to the observed stereoselectivity.
Conclusions
Although the first enantiopure mechanically planar chiral rotaxane was reported
over two decades ago,15 this is, to our knowledge, the first time that this stereogenic
unit has been applied in catalysis. The results presented clearly demonstrate that the
mechanically planar chiral stereogenic unit can direct enantioselective catalysis. The
results are particularly pleasing given that rotaxane 6 was not explicitly designed or
optimized for the reaction presented and yet achieves stereoselectivities with
benzoate esters of 42%–77% ee, comparable to a similar reaction mediated by opti-
mized covalent catalyst (R)-DTBM-SEGPHOS(AuCl)2 (68% ee). By extension, our re-
sults suggest that other mechanical stereogenic units6 such as the axial and topolog-
ical chiral units in catenanes have unexplored potential in catalytic applications.
However, the stereoselectivities observed in this cyclopropanation reaction are
lower than those reported when pivloate esters, which are not tolerated by
[Au(6)(Cl)], were employed with the best covalent catalysts (76% to 94% ee),41 clearly
demonstrating that challenges remain to be overcome for mechanically chiral
rotaxanes to become useful tools in organic synthesis. It should also be noted that
preliminary attempts to apply [Au(6)(Cl)] to other AuI-mediated reactions were un-
successful (see Supplemental Information), suggesting that our success in this one
reaction is serendipitous rather than an indication that the mechanically planar chiral
stereogenic unit is somehow
a ‘‘magic bullet’’ for enantioselective gold
catalysis. Indeed, this is consistent with results with covalent catalysts (e.g.,
(R)-DTBM-SEGPHOS(AuCl)2—see Supplemental Information) that have been
optimized for one AuI-mediated reaction but often perform poorly in others.45
Furthermore, despite recent progress in the area,38–40 the synthesis of mechanically
interlocked molecules is still challenging, in the example presented, specifically due
to the low stereoselectivity observed in the mechanical bond forming step and epi-
merization of the stereodirecting unit derived from the a-chiral azide that compli-
cates the purification. This synthetic challenge clearly complicates the optimization
of catalyst frameworks to deliver enhanced enantioselectivity. However, recent
progress in the development of new methodologies to access enantiopure mechan-
ically chiral molecules suggests that this synthetic challenge can and is being ad-
dressed, and pleasingly, based on the preliminary molecular modeling presented,
it seems that modern computational chemistry may well be able to aid the design
process.
Thus, in the future, we see a place for mechanical chirality in catalysis, particularly
where it is otherwise challenging to project chiral information into the reaction
space, as in the AuI-mediated reaction presented here; the crowded, three-dimen-
sional68,69 nature of the mechanical bond appears to be well suited to generating a
chiral pocket for chemical reactions to take place within, similar in some ways to
enzymatic active sites with their combination of steric hindrance and weak attractive
interactions with the substrate. Furthermore, combining chiral mechanical stereo-
genic units with the well-developed chemistry of interlocked molecular shut-
tles2,70–73 should allow the influence of the stereogenic mechanical bond to be
modulated74 in a stimuli-responsive manner in order to develop switchable chiral
10
Chem 6, 1–13, April 9, 2020

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
catalysts, for instance, to produce both hands of a given chiral product in high enan-
tioselectivity75,76 Indeed, during the preparation of this manuscript, this principle
was demonstrated in the context of co-conformational covalent point chirality.77
The same principles may also hold in the development of enantioselective sensors
for chiral molecules. What is clear, based on these results, is that the chemical appli-
cations78,79 of mechanically chiral interlocked molecules deserve further
investigation.
DATA AND CODE AVAILABILITY
The accession numbers for the solid-state structures of (S,Rmp)-4 and (S,Smp)-4 re-
ported in this paper are CCDC: 1950723, 1980985, respectively. Processed com-
pound characterization data are available freely from the University of Southampton
repository (https://doi.org/10.5258/SOTON/D1223).
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.02.006.
ACKNOWLEDGMENTS
S.M.G. thanks the European Research Council (consolidator grant agreement no.
724987) and Leverhulme Trust (ORPG-2733) for funding and the Royal Society for
a Research Fellowship. S.M.G. is a Royal Society Wolfson Research Fellow. The au-
thors would like to thank Dr. Marzia Galli and Dr. Jorge Meijide Suarez for helpful dis-
cussions and the latter for preparation of starting material S12. The authors thank Dr.
Graham Tizzard of the National Crystallographic Service for helpful discussions
around the SC-XRD data. The authors acknowledge the use of the IRIDIS High Per-
formance Computing Facility and associated support services at the University of
Southampton, in the completion of this work.
AUTHOR CONTRIBUTIONS
S.M.G. conceived the project and secured the project funding. A.W.H. contributed
to the design of the experiments and methodology and executed all of the experi-
mental procedures. S.M.G. carried out the computational modeling. S.M.G. wrote
the manuscript with input from A.W.H. Both authors contributed to the reviewing
and editing of the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: September 1, 2019
Revised: October 1, 2019
Accepted: February 10, 2020
Published: March 9, 2020
REFERENCES
1. Bruns, C.J., and Stoddart, J.F. (2016). The
Nature of the Mechanical Bond: From
Molecules to Machines (Wiley).
3. Stoddart, J.F. (2017). Mechanically interlocked
molecules (MIMs)-molecular shuttles, switches,
and machines (nobel lecture). Angew. Chem.
Int. Ed. 56, 11094–11125.
5. Feringa, B.L. (2017). The art of building small:
from molecular switches to motors (nobel
lecture). Angew. Chem. Int. Ed. 56, 11060–
11078.
2. Erbas-Cakmak, S., Leigh, D.A., McTernan, C.T.,
and Nussbaumer, A.L. (2015). Artificial
molecular machines. Chem. Rev. 115, 10081–
10206.
4. Sauvage, J.P. (2017). From chemical topology
to molecular machines (nobel lecture). Angew.
Chem. Int. Ed. 56, 11080–11093.
6. Jamieson, E.M.G., Modicom, F., and Goldup,
S.M. (2018). Chirality in rotaxanes and
catenanes. Chem. Soc. Rev. 47, 5266–5311.
Chem 6, 1–13, April 9, 2020
11

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
7. Frisch, H.L., and Wasserman, E. (1961).
Chemical topology1. J. Am. Chem. Soc. 83,
3789–3795.
[2]rotaxane molecular shuttle. J. Am. Chem.
Soc. 141, 9129–9133.
cages for asymmetric catalysis. Chemistry 25,
662–672.
21. Cakmak, Y., Erbas-Cakmak, S., and Leigh, D.A.
(2016). Asymmetric catalysis with a
37. Zhang, P., Tugny, C., Meijide Sua´rez, J., Guitet,
M., Derat, E., Vanthuyne, N., Zhang, Y., Bistri,
O., Mourie` s-Mansuy, V., Me´ nand, M., et al.
(2017). Artificial chiral metallo-pockets
8. Schill, G. (1971). Catenanes, Rotaxanes and
Knots (Academic Press).
mechanically point-chiral rotaxane. J. Am.
Chem. Soc. 138, 1749–1751.
9. Pairault, N., and Niemeyer, J. (2018). Chiral
mechanically interlocked molecules –
applications of rotaxanes, catenanes and
molecular knots in stereoselective
chemosensing and catalysis. Synlett 29,
689–698.
including a single metal serving as structural
probe and catalytic center. Chem 3, 174–191.
22. Goldup, S.M. (2016). Mechanical chirality: a
chiral catalyst with a ring to it. Nat. Chem. 8,
404–406.
38. Bordoli, R.J., and Goldup, S.M. (2014). An
efficient approach to mechanically planar chiral
rotaxanes. J. Am. Chem. Soc. 136, 4817–4820.
23. Alvarez-Pe´ rez, M., Goldup, S.M., Leigh, D.A.,
and Slawin, A.M.Z. (2008). A chemically-driven
molecular information ratchet. J. Am. Chem.
Soc. 130, 1836–1838.
10. Evans, N.H. (2018). Chiral catenanes and
rotaxanes: fundamentals and emerging
applications. Chemistry 24, 3101–3112.
39. Jinks, M.A., de Juan, A., Denis, M., Fletcher,
C.J., Galli, M., Jamieson, E.M.G., Modicom, F.,
Zhang, Z., and Goldup, S.M. (2018).
24. Carlone, A., Goldup, S.M., Lebrasseur, N.,
Leigh, D.A., and Wilson, A. (2012). A three-
compartment chemically-driven molecular
information ratchet. J. Am. Chem. Soc. 134,
8321–8323.
Stereoselective synthesis of mechanically
planar chiral rotaxanes. Angew. Chem. Int. Ed.
57, 14806–14810.
11. Da´laigh, C.O., Hynes, S.J., Maher, D.J., and
Connon, S.J. (2005). Kinetic resolution of sec-
alcohols using a new class of readily assembled
(S)-proline-derived 4-(pyrrolidino)-pyridine
analogues. Org. Biomol. Chem. 3, 981–984.
40. Denis, M., Lewis, J.E.M., Modicom, F., and
Goldup, S.M. (2019). An auxiliary approach for
the stereoselective synthesis of topologically
chiral catenanes. Chem 5, 1512–1520.
25. Eliel, E., Wilen, S., and Mander, L. (1994).
Stereochemistry of Organic Compounds (John
Wiley and Sons, Inc)).
12. Spivey, A.C., Zhu, F., Mitchell, M.B., Davey,
S.G., and Jarvest, R.L. (2003). Concise synthesis,
preparative resolution, absolute configuration
determination, and applications of an
26. By chirotopic elements, we mean stereogenic
units around that are locally chiral (see: Mislow,
K., and Siegel, J. (1984). Stereoisomerism and
local chirality J. Am. Chem. Soc. 106, 3319–
3328, Similarly, when we describe a molecule as
"mechanically planar chiral" (or similar) this is
shorthand for a molecule that is chiral as a
consequence of containing the mechanical
planar chiral stereogenic unit.
41. Johansson, M.J., Gorin, D.J., Staben, S.T., and
Toste, F.D. (2005). Gold(I)-catalyzed
atropisomeric biaryl catalyst for asymmetric
acylation. J. Org. Chem. 68, 7379–7385.
stereoselective olefin cyclopropanation. J. Am.
Chem. Soc. 127, 18002–18003.
13. Ruble, J.C., Latham, H.A., and Fu, G.C. (1997).
Effective kinetic resolution of secondary
alcohols with a planar-chiral analogue of 4-
(dimethylamino)pyridine. Use of the Fe(C5Ph5)
group in asymmetric catalysis. J. Am. Chem.
Soc. 119, 1492–1493.
42. Wang, Y.M., Lackner, A.D., and Toste, F.D.
(2014). Development of catalysts and ligands
for enantioselective gold catalysis. Acc. Chem.
Res. 47, 889–901.
27. Noyori, R. (2002). Asymmetric catalysis: science
and opportunities (nobel lecture). Angew.
Chem. Int. Ed. 41, 2008–2022.
43. Zi, W., and Dean Toste, F. (2016). Recent
advances in enantioselective gold catalysis.
Chem. Soc. Rev. 45, 4567–4589.
14. Crittall, M.R., Rzepa, H.S., and Carbery, D.R.
(2011). Design, synthesis, and evaluation of a
helicenoidal DMAP lewis base catalyst. Org.
Lett. 13, 1250–1253.
28. Knowles, W.S. (2002). Asymmetric
hydrogenations (nobel lecture). Angew. Chem.
Int. Ed. 41, 1999–2007.
44. Wang, Z., Nicolini, C., Hervieu, C., Wong, Y.F.,
Zanoni, G., and Zhang, L. (2017). Remote
cooperative group strategy enables ligands for
accelerative asymmetric gold catalysis. J. Am.
Chem. Soc. 139, 16064–16067.
15. Yamamoto, C., Okamoto, Y., Schmidt, T.,
29. Sharpless, K.B. (2002). Searching for new
reactivity (nobel lecture). Angew. Chem. Int.
Ed. 41, 2024–2032.
Jager, R., and Vogtle, F. (1997). Enantiomeric
¨
¨
resolution of cycloenantiomeric rotaxane,
topologically chiral catenane, and pretzel-
shaped molecules: observation of pronounced
circular dichroism. J. Am. Chem. Soc. 119,
10547–10548.
45. For a recent example of an elegant design
strategy to control the enantioselective folding
of an enyne substrate on a p-surface, as well as
where a very large number of previously
successful ligands for AuI enantioselective
catalysis were screened (often with poor
results) in a new reaction, see: Zuccarello, G.,
Mayans, J.G., Escofet, I., Scharnagel, D.,
Kirillova, M.S., Pe´ rez-Jimeno, A.H., Calleja, P.,
Boothe, J.R., and Echavarren, A.M. (2019).
Enantioselective folding of enynes by gold(I)
catalysts with a remote C2 -chiral element
J. Am. Chem. Soc. 141, 11858–11863.
30. Phipps, R.J., Hamilton, G.L., and Toste, F.D.
(2012). The progression of chiral anions from
concepts to applications in asymmetric
catalysis. Nat. Chem. 4, 603–614.
16. Kaida, Y., Okamoto, Y., Chambron, J.-C.,
Mitchell, D.K., and Sauvage, J.-P. (1993). The
separation of optically active copper (I)
31. Hong, Y., Jarrige, L., Harms, K., and Meggers,
E. (2019). Chiral-at-iron catalyst: expanding the
chemical space for asymmetric earth-abundant
metal catalysis. J. Am. Chem. Soc. 141, 4569–
4572.
catenates. Tetrahedron Lett. 34, 1019–1022.
17. Hirose, K., Ukimi, M., Ueda, S., Onoda, C.,
Kano, R., Tsuda, K., Hinohara, Y., and Tobe, Y.
(2018). The asymmetry is derived from
mechanical interlocking of achiral axle and
achiral ring components –syntheses and
properties of optically pure [2]rotaxanes–.
Symmetry 10, 20.
32. Yashima, E., Maeda, K., Iida, H., Furusho, Y.,
and Nagai, K. (2009). Helical polymers:
synthesis, structures, and functions. Chem. Rev.
109, 6102–6211.
46. Wang, Y., Zhang, P., Di, X., Dai, Q., Zhang, Z.M.,
and Zhang, J. (2017). Gold-catalyzed
asymmetric intramolecular cyclization of N-
Allenamides for the synthesis of chiral
Tetrahydrocarbolines. Angew. Chem. Int. Ed.
56, 15905–15909.
33. Boersma, A.J., Megens, R.P., Feringa, B.L., and
Roelfes, G. (2010). DNA-based asymmetric
catalysis. Chem. Soc. Rev. 39, 2083–2092.
18. Ishiwari, F., Nakazono, K., Koyama, Y., and
Takata, T. (2017). Induction of Single-Handed
helicity of polyacetylenes using mechanically
chiral rotaxanes as chiral sources. Angew.
Chem. Int. Ed. 56, 14858–14862.
34. Silverman, S.K. (2010). DNA as a versatile
chemical component for catalysis, encoding,
and stereocontrol. Angew. Chem. Int. Ed. 49,
7180–7201.
47. Galli, M., Lewis, J.E.M., and Goldup, S.M.
(2015). A stimuli-responsive Rotaxane-gold
catalyst: regulation of activity and
diastereoselectivity. Angew. Chem. Int. Ed. 54,
13545–13549.
19. Mochizuki, Y., Ikeyatsu, K., Mutoh, Y., Hosoya,
S., and Saito, S. (2017). Synthesis of
mechanically planar chiral rac- [2]rotaxanes by
partitioning of an achiral [2]rotaxane:
stereoinversion induced by shuttling. Org. Lett.
19, 4347–4350.
35. Nagata, Y., Takeda, R., and Suginome, M.
(2019). Asymmetric catalysis in chiral solvents:
chirality transfer with amplification of
homochirality through a helical
48. Lahlali, H., Jobe, K., Watkinson, M., and
Goldup, S.M. (2011). Macrocycle size matters:
‘‘small’’ functionalized rotaxanes in excellent
yield using the CuAAC active template
approach. Angew. Chem. Int. Ed. 50, 4151–
4155.
macromolecular scaffold. ACS Cent. Sci. 5,
1235–1240.
20. Corra, S., de Vet, C., Groppi, J., La Rosa, M.,
Silvi, S., Baroncini, M., and Credi, A. (2019).
Chemical on/off switching of mechanically
planar chirality and chiral anion recognition in a
36. Tan, C., Chu, D., Tang, X., Liu, Y., Xuan, W., and
Cui, Y. (2019). Supramolecular coordination
12
Chem 6, 1–13, April 9, 2020

Please cite this article in press as: Heard and Goldup, Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.006
49. Denis, M., and Goldup, S.M. (2017). The active
template approach to interlocked molecules.
Nat. Rev. Chem. 1, 0061.
59. The absolute stereochemistry of (1S,2R)-9 was
assigned by comparison with the product of
the reaction mediated by (R)-DTBM-
mechanical bond, see: Tachibana, Y., Kihara,
N., and Takata, T. (2004). Asymmetric benzoin
condensation catalyzed by chiral rotaxanes
tethering a thiazolium salt moiety via the
cooperation of the component: can rotaxane
be an effective reaction field? J. Am. Chem.
Soc. 126, 3438–3439.
SEGPHOSꢀ(AuCl)2, the stereochemical
outcome of which is known.41 The absolute
configurations of cis-15, cis-16, and cis-18 were
determined to be (1S,2R) by convergence to
the same reduction product as that produced
by cis-9 (see Supplemental Information for
details). The absolute stereochemistry of all
other cyclopropane products was not
50. Aucagne, V., Hanni, K.D., Leigh, D.A., Lusby,
¨
P.J., and Walker, D.B. (2006). Catalytic ‘‘click’’
rotaxanes: a substoichiometric metal-template
pathway to mechanically interlocked
architectures. J. Am. Chem. Soc. 128, 2186–
2187.
69. Xu, K., Nakazono, K., and Takata, T. (2016).
Design of Rotaxane Catalyst for O -Acylative
Asymmetric Desymmetrization of meso -1,2-
diol Utilizing the Cooperative Effect of the
Components. Chem. Lett. 45, 1274–1276.
51. Aucagne, V., Berna, J., Crowley, J.D., Goldup,
determined. The (1S,2R) products are shown
but this assignment is arbitrary.
S.M., Hanni, K.D., Leigh, D.A., Lusby, P.J.,
¨
Ronaldson, V.E., Slawin, A.M.Z., Viterisi, A., and
Walker, D.B. (2007). Catalytic ‘active-metal’
template synthesis of [2]rotaxanes, [3]
rotaxanes, and molecular shuttles, and some
observations on the mechanism of the cu(i)-
catalyzed azide-alkyne 1,3-cycloaddition.
J. Am. Chem. Soc. 129, 11950–11963.
60. Mitra, R., Zhu, H., Grimme, S., and Niemeyer, J.
(2017). Functional mechanically interlocked
molecules: asymmetric organocatalysis with a
catenated bifunctional brønsted acid. Angew.
Chem. Int. Ed. 56, 11456–11459.
70. For examples of switchable catalysts based on
rotaxane molecular shuttles, see: Blanco, V.,
Carlone, A., Hanni, K.D., Leigh, D.A., and
¨
Lewandowski, B. (2012). A rotaxane-based
switchable organocatalyst Angew. Chem. Int.
Ed. 51, 5166–5169.
61. Pe´ rez-Gala´n, P., Herrero-Go´ mez, E., Hog, D.T.,
Martin, N.J.A., Maseras, F., and Echavarren,
A.M. (2011). Mechanism of the gold-catalyzed
cyclopropanation of alkenes with 1,6-enynes.
Chem. Sci. 2, 141–149.
52. Lewis, J.E.M., Bordoli, R.J., Denis, M., Fletcher,
C.J., Galli, M., Neal, E.A., Rochette, E.M., and
Goldup, S.M. (2016). High yielding synthesis of
2,20-bipyridine macrocycles, versatile
71. Blanco, V., Leigh, D.A., Lewandowska, U.,
Lewandowski, B., and Marcos, V. (2014).
Exploring the activation modes of a Rotaxane-
based switchable organocatalyst. J. Am.
Chem. Soc. 136, 15775–15780.
intermediates in the synthesis of rotaxanes.
Chem. Sci. 7, 3154–3161.
62. It is an open question whether an interlocked
molecule in which the components are bridged
in this manner are true rotaxanes or if the
metal-ligand interactions constitute a covalent
link, rendering them entangled but not
mechanically bonded, strictly speaking.
Sauvage employed the term ‘‘catenate’’ to
denote such complexes in the context of
catenanes,16 but the equivalent noun
53. Care must be taken in the separation of
diastereomers 4 as the covalent stereogenic
center is prone to epimerization. See
72. Eichstaedt, K., Jaramillo-Garcia, J., Leigh, D.A.,
Marcos, V., Pisano, S., and Singleton, T.A.
(2017). Switching between anion-binding
catalysis and aminocatalysis with a rotaxane
dual-function catalyst. J. Am. Chem. Soc. 139,
9376–9381.
Supplemental Information for full details
54. Although the SC-XRD-derived solid state
structure of (S,Rmp)-4 is of high quality, the
single-crystal of (S,Smp)-4 appears to be
contaminated with an oxidized derivative of the
rotaxane. The structure of (S,Rmp)-4 alone is
sufficient to assign the relative and, using the
known stereochemistry of the azide derived
component, the absolute stereochemistry of
both diastereomers. However, the SC-XRD-
derived structure of (S,Smp)-4 is of good
quality once the impurity is taken into account
and, importantly, the relative stereochemistry
observed is, as expected, epimeric with that
determined for (S,Rmp)-4. For full details, see
Supplemental Information.
‘‘rotaxanate’’ is more commonly used as a verb
meaning ‘‘to make a rotaxane.’’ For examples
where rotaxanate is used as a noun, see:
Furusho, Y., Matsuyama, T., Takata, T.,
Moriuchi, T., and Hirao, T. (2004). Synthesis of
novel interlocked systems utilizing a palladium
complex with 2,6-pyridinedicarboxamide-
based tridentate macrocyclic ligand
73. Blanco, V., Leigh, D.A., Marcos, V., Morales-
Serna, J.A., and Nussbaumer, A.L. (2014). A
switchable [2]rotaxane asymmetric
organocatalyst that utilizes an acyclic chiral
secondary amine. J. Am. Chem. Soc. 136,
4905–4908.
74. Suzuki, S., Ishiwari, F., Nakazono, K., and
Takata, T. (2012). Reversible helix–random coil
transition of poly(m-phenylenediethynylene) by
a rotaxane switch. Chem. Commun. (Camb.)
48, 6478–6480.
Tetrahedron Lett. 45, 9593–9597.
63. Mateo-Alonso, A. (2010). Mechanically
interlocked molecular architectures
functionalised with fullerenes. Chem.
Commun. (Camb.) 46, 9089–9099.
75. For examples of non-interlocked molecular
machines that control the stereoselective
synthesis of molecules, see: Wang, J., and
Feringa, B.L. (2011). Dynamic control of chiral
space in a catalytic asymmetric reaction using a
molecular motor Science 331, 1429–1432.
55. SC-XRD allows the relative stereochemistry of
the mechanical bond and covalent stereogenic
unit to be determined unambiguously for the
diastereomeric rotaxanes. This information,
combined with the known configuration of the
azide-derived stereogenic unit, allows the
absolute stereochemistry of rotaxanes 4, and
their derivatives, to be determined
64. Miyagawa, N., Watanabe, M., Matsuyama, T.,
Koyama, Y., Moriuchi, T., Hirao, T., Furusho, Y.,
and Takata, T. (2010). Successive catalytic
reactions specific to Pd-based rotaxane
complexes as a result of wheel translation
along the axle. Chem. Commun. (Camb.) 46,
1920–1922, Here we use the term
76. Kassem, S., Lee, A.T.L., Leigh, D.A., Marcos, V.,
Palmer, L.I., and Pisano, S. (2017).
Stereodivergent synthesis with a
programmable molecular machine. Nature
549, 374–378.
‘‘metallorotaxane,’’ which has seen some use to
denote the mechanically chelated complex,
rather than "rotaxanate," to avoid confusion.1.
56. Miki, K., Ohe, K., and Uemura, S. (2003). A new
ruthenium-catalyzed cyclopropanation of
alkenes using propargylic acetates as a
precursor of vinylcarbenoids. Tetrahedron Lett.
44, 2019–2022.
65. Wavefunction Inc. and Q-Chem (2010).
Spartan’10 (Wavefunction Inc).
77. Dommaschk, M., Echavarren, J., Leigh, D.A.,
Marcos, V., and Singleton, T.A. (2019). Dynamic
control of chiral space Through local symmetry
breaking in a rotaxane organocatalyst. Angew.
Chem. Int. Ed. 58, 14955–14958.
57. Teller, H., Flugge, S., Goddard, R., and
¨
66. Frisch, M.J., Trucks, G.W., Schlegel, H.B.,
Scuseria, G.E., Robb, M.A., Cheeseman, J.R.,
Scalmani, G., Barone, V., Mennucci, B.,
Petersson, G.A., et al. (2016). Gaussian 09,
Revision A.02 (Gaussian, Inc.).
Furstner, A. (2010). Enantioselective gold
¨
catalysis: opportunities provided by
monodentate phosphoramidite ligands with an
acyclic TADDOL backbone. Angew. Chem. Int.
Ed. 49, 1949–1953.
78. Sluysmans, D., and Stoddart, J.F. (2019). The
burgeoning of mechanically interlocked
molecules in chemistry. Trends Chem. 1,
185–197.
67. Single point energy calculation based on the
gas phase 6–31G* structure; transition state
optimization using the 6–31G* basis set in
solvent proved prohibitively computationally
expensive
58. Gross, E., Liu, J.H., Alayoglu, S., Marcus, M.A.,
Fakra, S.C., Toste, F.D., and Somorjai, G.A.
(2013). Asymmetric catalysis at the mesoscale:
gold nanoclusters embedded in chiral self-
assembled monolayer as heterogeneous
79. Heard, A.W., and Goldup, S.M. (2020).
Simplicity in the design, operation and
applications of mechanically interlocked
molecular machines. ACS Cent. Sci.
catalyst for asymmetric reactions. J. Am. Chem. 68. For examples in which covalent chiral
Soc. 135, 3881–3886. information is transferred through the
Chem 6, 1–13, April 9, 2020
13