Tying a Molecular Overhand Knot of Single Handedness and Asymmetric Catalysis with the Corresponding Pseudo-D3-Symmetric Trefoil Knot

Article abstract of DOI:10.1021/jacs.6b08421

We report the stereoselective synthesis of a left-handed trefoil knot from a tris(2,6-pyridinedicarboxamide) oligomer with six chiral centers using a lanthanide(III) ion template. The oligomer folds around the lanthanide ion to form an overhand knot complex of single handedness. Subsequent joining of the overhand knot end groups by ring-closing olefin metathesis affords a single enantiomer of the trefoil knot in 90% yield. The knot topology and handedness were confirmed by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The pseudo-D₃-symmetric knot was employed as an asymmetric catalyst in Mukaiyama aldol reactions, generating enantioselectivities of up to 83:17 er, which are significantly higher than those obtained with a comparable unknotted ligand complex.

Full text of DOI:10.1021/jacs.6b08421

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Communication
Tying a Molecular Overhand Knot of Single Handedness and Asymmetric
3
Catalysis with the Corresponding Pseudo-D-Symmetric Trefoil Knot
Guzman Gil-Ramirez, Steven Hoekman, Matthew O Kitching,
David A. Leigh, Inigo J. Vitorica-Yrezabal, and Gen Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08421 • Publication Date (Web): 26 Sep 2016
Downloaded from http://pubs.acs.org on September 26, 2016
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Tying a Molecular Overhand Knot of Single Handedness and
Asymmetric Catalysis with the Corresponding Pseudo-D3-
Symmetric Trefoil Knot
Guzmán Gil-Ramírez,† Steven Hoekman,† Matthew O. Kitching,† David A. Leigh,* Iñigo J. Vi-
torica-Yrezabal, and Gen Zhang†
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School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
Supporting Information Placeholder
mer about a zinc(II) ion template to form a racemic over-
ABSTRACT: We report the stereoselective synthesis of a
hand knot,5g,12 we envisioned that it might be possible to tie
left-handed
trefoil
knot
from
a
tri(2,6-
an overhand knot of defined stereochemistry in a molecular
strand using a chiral tri(2,6-pyridinedicarboxamide) oligo-
mer and a lanthanide(III) ion template. Subsequently joining
the ends of the overhand knot together would give a chiral
trefoil knot.
pyridinedicarboxamide) oligomer with six chiral centers us-
ing a lanthanide(III) ion template. The oligomer folds around
the lanthanide ion to form an overhand knot complex of
single handedness. Subsequent joining of the overhand knot
end groups by ring-closing olefin metathesis affords a single
stereoisomer of the trefoil knot in 90% yield. The knot topol-
ogy and handedness was confirmed by NMR spectroscopy,
mass spectrometry and X-ray crystallography. The pseudo-
D3-symmetric knot was employed as an asymmetric catalyst
in Mukaiyama aldol reactions, generating enantioselectivities
of up to 83:17 er, significantly higher than those obtained
with a comparable unknotted ligand complex.
Scheme 1. Synthesis of Molecular Overhand Knots, Λ-
Lu/Eu(R6)-1(CF3SO3)3, and Trefoil Knots, Λ-Lu/Eu(R6)-
2, of Single Handednessa
a
b
O
O
O
O
O
O
N
N
N
e
c
NH HN
NH HN
NH HN
d
Knotted regions of proteins can play a significant role in
ligand binding1 and alter enzymatic activity compared to
unknotted homologues.2 The chemical effects of knotting in
synthetic molecular systems, however, have to date been less
explored.3 The simplest non-trivial knot, the trefoil knot, has
three crossing points and is topologically chiral.4 Although a
number of synthetic strategies to racemic trefoil knots have
been developed,5,6 there are few examples of their stereose-
lective synthesis.7 Here we describe the assembly of a trefoil
knot of single handedness by entwining a ligand strand with
six asymmetric carbon atoms around a lanthanide ion tem-
plate.8 We find that the chiral trefoil knot is an effective cata-
lyst for the asymmetric Mukaiyama aldol reaction. As far as
we are aware this is the first example of a chiral molecular
knot being utilized in asymmetric catalysis.9,10
O
O
O
O
O
O
O
O
O
O
(R6)ꢀ1
a
3+
3 CF3SO3‾
3+
3 CF3SO3‾
O
O
O
O
H
N
H
N
H
H
b
N
N
N
N
O
O
O
O
O
O
O
O
HN
HN
NH
NH
Ln
Ln
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
NH
O
NH
O
O
O
O
ΛꢀLn(R6)ꢀ2
ΛꢀLn(R6)ꢀ1
We recently described7d the assembly of three chiral 2,6-
pyridinedicarboxamide ligands about a lanthanide metal ion
to form a circular helicate.11 By joining the ligands’ end
groups a trefoil knot of single handedness was obtained, the
point chirality of the ligands determining the topological
handedness of the knot. Following Hunter’s synthesis of a
racemic trefoil knot by entwining a flexible bipyridine oligo-
Ln = Lu or Eu
a Reagents and conditions: (a) Eu(CF3SO3)3, CH3CN, 80 oC, 12
h, 85% or Lu(CF3SO3)3, 80 oC, 12 h, 90%; (b) Hoveyda-Grubbs
2nd generation catalyst (15 mol%), CH2Cl2/CH3NO2, 50 C, 18
o
h, 88% Λ-Lu(R6)-2(CF3SO3)3, 90% Λ-Eu(R6)-2(CF3SO3)3.
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field with respect to those in (R6)-1 (ꢀδH = 0.89 and 1.96
ppm), indicative of π-π stacking between the pyridine and
Our previous Ln-template chiral trefoil knot was pre-
pared7d using ring closing olefin metathesis (RCM) to simul-
taneously form ten-atom linkers between each pair of the
three 2,6-pyridinedicarboxamide units. To maintain a similar
spacer length13 in the tri(2,6-pyridinedicarboxamide) oligo-
mer we used triethylene glycol groups to connect the end
sections to the central ligand set, generating ligand (R6)-1
(see Supporting Information).
a
naphthalene rings. The Hd protons are also upfield shifted
(ꢀδ = 0.63 and 0.73 ppm) and split into two different signals.
To join the two end groups of the overhand knot, Λ-
Lu(R6)-1(CF3SO3)3 was treated with the second generation
Hoveyda-Grubbs catalyst in CH2Cl2/CH3NO2 (3:1, v/v) at
50 °C for 18 h (Scheme 1, step b). Quenching of the reaction
with ethyl vinyl ether, followed by addition of dichloro-
methane, precipitated trefoil knot complex Λ-Lu(R6)-
9
Ligand (R6)-1 was treated with Lu(CF3SO3)3 in CD3CN and
the overhand knot tying process (Scheme 1, step a) followed
by 1H NMR spectroscopy (Figure 1). Although the assembly of
discrete 2,6-pyridinedicarboxamide ligands about a lantha-
nide(III) ion is typically fast, even at room temperature,7d,14
the 1H NMR spectrum of (R6)-1 in the presence of
Lu(CF3SO3)3 was initially broad (Figure 1b). However, heating
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1
2(CF3SO3)3. The H NMR spectrum (Figure 1d) lacks the ter-
minal alkene protons of Λ-Lu(R6)-1(CF3SO3)3 (Figure 1c) and
features fewer sets of resonances than the overhand knot, a
reflection of the trefoil knot being essentially D3-symmetric
other than for one of the three linker groups being different
to the other two. Electrospray ionization mass spectrometry
confirmed the intramolecular ring closure (ESI-MS; m/z 1060
[Lu(R6)-2][CF3SO3]2+, 657 [Lu(R6)-2]3+).
o
1
the solution at 80 C led to a sharp H NMR spectrum after
several hours (Figure 1c) indicating slow equilibration to pre-
dominantly a single species. This was shown to be the over-
hand knot complex, Λ-Lu(R6)-1(CF3SO3)3, by a combination
of electrospray ionization mass spectrometry (ESI-MS; m/z
1074 [Lu(R6)-1][CF3SO3]2+, 666 [Lu(R6)-1]3+) and 1H NMR
spectroscopy (Figure 1c).
Substituting Eu(CF3SO3)3 for Lu(CF3SO3)3 in the reactions
shown in Scheme 1 generated the corresponding europium
trefoil knot complex, Λ-Eu(R6)-2(CF3SO3)3 (see Supporting
Information). Slow diffusion of diethyl ether into a saturated
methanolic solution of Λ-Eu(R6)-2(CF3SO3)3 afforded single
crystals suitable for X-ray diffraction. The solid state X-ray
structure confirmed the molecular topology and showed that
the trefoil knot is of Λ-handedness (Figure 2 and Supporting
Information). The knotted ligand wraps around the europi-
um ion to give a trigonal prismatic coordination geometry
with the Eu-O (2.33 and 2.39 Å) and Eu-N (2.52 Å) distances
in
the
expected
ranges
for
europium-2,6-
pyridinedicarboxamide complexes.7d,15 Aromatic stacking
between each pyridine ring and two naphthalene groups
hold the ligand in a compact arrangement around the metal
1
ion. The solid state structure is consistent with the H NMR
shielding observed in solution (Figure 1).
1
Figure 1. Selected regions of the H NMR spectra (600 MHz,
CD3CN, 295 K [345 K for (a) and (c)]) of: (a) ligand strand
(R6)-1; (b) equimolar mixture of oligomer (R6)-1 and
Lu(CF3SO3)3 after 5 min at rt; (c) left-handed overhand knot
complex Λ-Lu(R6)-1(CF3SO3)3; (d) left-handed trefoil knot
complex Λ-Lu(R6)-2(CF3SO3)3. The signals shown in red cor-
respond to the protons in the pyridine rings and -NHCHCH3-
fragments. The lettering refers to the proton assignments
shown in Scheme 1. * = water
Figure 2. (a) X-Ray crystal structure of Λ-Eu(R6)-2(CF3SO3)3
shown in framework representation. Hydrogen atoms, sol-
vent molecules and counter-anions are omitted for clarity.
Selected metal-donor atom bond lengths (Å): Eu-O 2.33(2) x
3, 2.39(2) x 3; Eu-N 2.52(2) x 2, 2.52(1).
1
The H NMR spectrum of Λ-Lu(R6)-1(CF3SO3)3 (Figure 1c)
features several different environments for each set of pro-
tons Ha, Hb, Hc, Hd and He, consistent with the pronounced
asymmetric environment provided by the overhand knot.
Pyridine ring protons Ha and Hb are significantly shifted up-
Ligand 2 is a rare example of an enantiomerically pure tre-
foil knot.6,7 A pentafoil knot was recently employed in anion
binding catalysis16 but the chirality of molecular knots has
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not previously been exploited in asymmetric catalysis. As
respectively, indicating that a solvent molecule rapidly and
reversibly binds to the lanthanide ion despite it being at the
center of the trefoil knot.22 As the metal ion remains accessi-
ble whilst bound within the chiral pocket of the knot it may
be that the Mukaiyama aldol reaction is promoted through
coordination of the aldehyde to the lanthanide.23 In contrast,
Λ-Eu-6 gave q values of 0.9 and 3.3, indicative of two species
in slow exchange, one bound to one solvent molecule and
one bound to three. Presumably the more highly solvated
lanthanide ion results from transient loss of one of the 2,6-
pyridinedicarboxamide groups. The continuous covalent
backbone of the knotted ligand thus helps to maintain the
well-defined chiral environment around the lanthanide ion
which, in turn, may help to maximize the enantiomeric en-
richment of the syn- product.
lanthanide salts have been widely used as Lewis acids to
promote asymmetric Mukaiyama aldol reactions, in some
cases with high enantioselectivies,17 we first investigated the
efficacy of Λ-Eu(R6)-2(CF3SO3)3 as a chiral catalyst for the
reaction of 4-nitrobenzaldehyde 3 with silyl enol ether 4
(Figure 3).18 Solvent choice proved crucial for the catalysis;19
methanol:acetonitrile (5:2) giving both the highest conver-
sions and the most promising levels of enantioenrichment. In
comparison to both open complex Λ-Eu-6 (Figure 3 ta-
ble, entry 2) and the previously reported7d trefoil knot, Λ-Eu-
7 (Figure 3 table, entry 3), Λ-Eu(R6)-2 generated product 5
with improved (65:35 er) enantiomeric enrichment (Figure 3
table, entry 1). In each case enrichment was observed only in
the syn-diastereomer,20 with the anti-diastereomer formed
racemically.21 Introducing additional steric bulk into the enol
ether (8) improved the enantioselectivity (83:17 er for syn-9,
Figure 4). Less activated aldehydes (replacing NO2 with H or
Me) gave lower yields and favored the anti-adduct (10 and 11,
Figure 4), although the degree of enantioselectivity in the
syn-diastereomer was maintained. p-Bromoaldehyde proved
essentially unreactive under the reaction conditions em-
ployed (12, Figure 4).
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Figure 4. Chiral trefoil knot Λ-Eu(R6)-2(CF3SO3)3 catalyzed
asymmetric Mukaiyama aldol reactions. Reaction conditions:
1.0 equiv. of aldehyde and 1.5 equiv. trimethyl(3-methyl-1-
phenylbutenyloxy)silane at −10 °C for 4 d. aDetermined by 1H
b
NMR. Determined by chiral HPLC. In all cases the relative
stereochemistry of the most enantioenriched diastereomer is
shown.
In summary, the stereochemistry of chiral centers within a
ligand strand has been used to control the handedness of an
overhand knot tied in the strand through complexation with
a lanthanide ion. Joining the ends of the overhand knot by
RCM resulted in a trefoil knot of single handedness in 90%
yield. The chiral trefoil knot-lanthanide complex is an effec-
tive catalyst for the asymmetric Mukaiyama aldol reaction.
The ability to tie knots of single handedness in molecular
strands should facilitate the investigation of topological ste-
reochemistry in fields where the transfer of chiral infor-
mation is important (such as asymmetric catalysis, chiral
recognition, chiral liquid crystal phases and materials for
nonlinear optics).
Entry Catalyst
Solvent
Conv. syn:anti a syn-
(%)a er (%)b
6
1
MeOH/CH CN 61
1 : 1
65:35
58:42
54:46
-
Λ-Eu(R )-2
Λ-Eu-6
Λ-Eu-7
-
3
2
3
4
MeOH/CH3CN 61
MeOH/CH3CN 65
MeOH/CH3CN 17
1 : 1
1 : 1.4
1 : 1
Figure 3. Europium-ligand catalyzed Mukaiyama aldol reac-
tions. Reaction conditions: 4-nitrobenzaldehyde (1.0 equiv.),
trimethyl(1-phenylpropenyloxy)silane (1.0 equiv.) at −10 °C
ASSOCIATED CONTENT
Supporting Information
1
for 4 d. aDetermined by H NMR. bDetermined by chiral
Synthetic procedures, X-ray, NMR and MS characterization
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
HPLC.
To probe the mechanism of enantioselective knot catalysis
we determined the accessibility of the lanthanide ion bound
within the chiral pocket of the knot. Luminescence decay
lifetime measurements22 in MeOH and MeOD were used to
determine the number of solvent molecules bound to the
lanthanide core of complexes Λ-Eu(R6)-2, Λ-Eu-6 and Λ-Eu-7
(see Supporting Information). For the trefoil knots, Λ-
Eu(R6)-2 and Λ-Eu-7, q values of 0.8 and 1.1 were obtained,
AUTHOR INFORMATION
Corresponding Author
David.Leigh@manchester.ac.uk.
Notes
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† These authors contributed equally. The authors declare no
competing financial interests.
(7) (a) Perret-Aebi, L.-E.; von Zelewsky, A.; Dietrich-Buchecker, C.;
Sauvage, J.-P. Angew. Chem., Int. Ed. 2004, 43, 4482–4485. (b) Feigel,
M.; Ladberg, R.; Engels, S.; Herbst-Irmer, R.; Fröhlich, R. Angew.
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F. B. L.; Clough, J. M.; Pantoş, G. D.; Sanders, J. K. M. Science 2012,
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Browne, C.; Vitorica-Yrezabal, I. J.; Leigh, D. A. J. Am. Chem. Soc.
2015, 137, 10437–10442.
(8) For lanthanide template synthesis of other interlocked molecular
architectures, see: (a) Lincheneau, C.; Jean-Denis, B.; Gunnlaugsson,
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ACKNOWLEDGMENTS
We thank the European Research Council (ERC) and Engi-
neering and Physical Sciences Research Council (EPSRC) for
funding (EP/H021620/2), the EPSRC National Mass Spec-
trometry Service Centre (Swansea, U.K.) for high-resolution
mass spectrometry, and Dr Louise Natrajan and Dr Jennifer
E. Jones for their assistance with lifetime measurements.
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2016, 7, 2524–2531. For other small-molecule knots, see: (m) Ayme, J.-
F.; Beves, J. E.; Leigh, D. A.; McBurney, R. T.; Rissanen, K.; Schultz,
D. Nat. Chem. 2012, 4, 15−20. (n) Ayme, J.-F.; Beves, J. E.; Leigh, D. A.;
McBurney, R. T.; Rissanen, K.; Schultz, D. J. Am. Chem. Soc. 2012, 134,
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Soc. 2015, 137, 9812–9815.
(17) (a) Giuseppone, N.; Van de Weghe, P.; Mellah, M.; Collin, J.
Tetrahedron 1998, 54, 13129–13148. (b) Hatanaka, M.; Morokuma, K. J.
Am. Chem. Soc. 2013, 135, 13972–13979.
(18) In the catalysis studies Λ-Lu(R6)-2(CF3SO3)3 gave similar results
to Λ-Eu(R6)-2(CF3SO3)3.
(19) (a) Kobayashi, S. Pure Appl. Chem. 2007, 79, 235–245. (b) Mei, Y.;
Averill, D. J.; Allen, M. J. J. Org. Chem. 2012, 77, 5624–5632.
(20) The relative stereochemistry of the products was assigned
through comparison of 5 and 11 to literature values see; (a) Shibata,
I.; Suwa, T.; Sakakibara, H.; Baba, A. Org. Lett. 2002, 4, 301–303. (b)
Ohtsuka, Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org. Lett. 2001, 3,
2543–2546.
(21) For general principles in assigning syn vs anti diastereomers see:
Hen, K. K.; Simpson, J.; Smith, R. A. J.; Robinson, W. T. J. Org. Chem.
1981, 46, 2932–2934.
(6) For the separation of molecular knot enantiomers, see: (a)
Rapenne, G.; Dietrich-Buchecker, C.; Sauvage, J.-P. J. Am. Chem. Soc.
1996, 118, 10932–10933. (b) Dietrich-Buchecker, C.; Rapenne, G.;
Sauvage, J.-P.; De Cian, A.; Fischer, J. Chem. Eur. J. 1999, 5, 1432–1439.
(c) Vögtle, F.; Hünten, A.; Vogel, E.; Buschbeck, S.; Safarowsky, O.;
Recker, J.; Parham, A.-H.; Knott, M.; Müller, W. M.; Müller, U.;
Okamoto, Y.; Kubota, T.; Lindner, W.; Francotte, E.; Grimme, S.
Angew. Chem., Int. Ed. 2001, 40, 2468–2471.
(22) Supkowski, R. M.; Horrocks Jr, W. D. Inorg. Chim. Acta. 2002,
340, 44−48.
(23) We cannot rule out hydrogen bonding activation of the alde-
hyde from the amide group on the knot exterior as the mode of ca-
talysis, but this mode of activation seems unlikely as enantioselectiv-
ities are improved using methanol as a co-solvent as opposed to
solely non-hydrogen bonding solvents.
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