Stereoselective Synthesis of Molecular Square and Granny Knots

Article abstract of DOI:10.1021/jacs.9b01819

We report on the stereoselective synthesis of both molecular granny and square knots through the use of lanthanide-complexed overhand knots of specific handedness as three-crossing "entanglement synthons". The composite knots are assembled by combining two entanglement synthons (of the same chirality for a granny knot; of opposite handedness for a square knot) in three synthetic steps: first, a CuAAC reaction joins together one end of each overhand knot. Ring-closing olefin metathesis (RCM) then affords the closed-loop knot, locking the topology. This allows the lanthanide ions necessary for stabilizing the entangled conformation of the synthons to subsequently be removed. The composite knots were characterized by ¹H and ¹³C NMR spectroscopy and mass spectrometry and the chirality of the knot stereoisomers compared by circular dichroism. The synthetic strategy of combining building blocks of defined stereochemistry (here overhand knots of λ- or Δ-handed entanglement) is reminiscent of the chiron approach of using minimalist chiral synthons in the stereoselective synthesis of molecules with multiple asymmetric centers.

Full text of DOI:10.1021/jacs.9b01819

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Article
Stereoselective Synthesis of Molecular Square and Granny Knots
David A. Leigh, Lucian Pirvu, and Fredrik Schaufelberger
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01819 • Publication Date (Web): 20 Mar 2019
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Stereoselective Synthesis of Molecular Square and Granny Knots
David A. Leigh*, Lucian Pirvu, and Fredrik Schaufelberger
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School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Supporting Information Placeholder
crossing entanglement with an over-under-over-under-over-under
ABSTRACT: We report on the stereoselective synthesis of both
molecular granny and square knots through the use of lanthanide-
complexed overhand knots of specific handedness as three-
crossing ‘ entanglement synthons ’ . The composite knots are
assembled by combining two entanglement synthons (of the same
chirality for a granny knot; of opposite handedness for a square
knot) in three synthetic steps: First, a CuAAC reaction joins
together one end of each overhand knot. Ring-closing olefin
metathesis (RCM) then affords the closed-loop knot, locking the
topology. This allows the lanthanide ions necessary for stabilizing
the entangled conformation of the synthons to subsequently be
crossing sequence) of the same handedness (- or -) forms a
single enantiomer of a granny knot (-31#-31 or +31#+31)1a,3
,
whereas combining trefoil tangles of opposite handedness forms
the diastereomeric, topologically achiral, square knot (+31#-31)1a,3
(Figure 1b).
meso
a
1
removed. The composite knots were characterized by H and 13C
NMR spectroscopy and mass spectrometry, and the chirality of
the knot stereoisomers compared by circular dichroism. The
synthetic strategy of combining building blocks of defined
stereochemistry (here overhand knots of - or -handed
entanglement) is reminiscent of the chiron approach of using
minimalist chiral synthons in the stereoselective synthesis of
molecules with multiple asymmetric centers.
Diastereomers
+
X
X
Enantiomers
meso


b
INTRODUCTION
+31#-31 Square knot
Diastereomers
Most of the small-molecule knots1 synthesized to date are
trefoil2 (31)3 knots, the simplest non-trivial knot topology. The
few examples of more complex synthetic molecular knots4,5 are
highly symmetrical,6 with the strand crossings assembled in one
or two steps using frameworks designed to only tolerate the
particular crossing pattern required. Unfortunately such strategies
are not extendable to many knot topologies, which often lack
sufficient symmetry in their crossing arrangements. Alternative
synthetic approaches will need to be developed in order to access
at the molecular level the majority of knot topologies.1a
+




-31#-31 Granny knot
Enantiomers
+31#+31 Granny knot
Knots are topologically distinct from each other in terms of the
number of times a strand crosses itself, the arrangement (relative
stereochemistry) of each crossing compared to other crossings,
and the handedness (chirality) of the crossing sequence as a
whole.1a,3 Constitutionally identical but differently knotted
molecular strands are thus stereoisomers. The stereochemical
relationship between strand crossings in knots is somewhat
reminiscent of that between asymmetric centers in orthodox
organic molecules (Figure 1): The topological stereoisomerism of
knots is determined by the relative orientation (over, under) of
each strand crossing; conventional organic stereoisomerism is
determined by the relative handedness of stereogenic elements
(centers, planes, axes, helices, etc). For example, the dimerization
of a molecular fragment with an (R)-asymmetric center gives an
(R,R)-molecule which is the enantiomer of the (S)-building block
dimer and a diastereomer of the meso- (R,S)-compound (Figure
1a). In the case of knots, joining two trefoil tangles (a three-
Figure 1. Parallels in the structural relationship between
asymmetric centers in chiral molecules and strand crossings in
knots. (a) Stereochemical consequences of combining two one-
asymmetric-center synthons. (b) Topological consequences of
combining two three-crossing entanglement synthons.
Granny and square knots are examples of composite knots, that
is closed-loops consisting of two or more ring-opened prime knots
joined together.3 The synthesis of composite knots5 is complicated
by the difficulty in controlling knotting stereochemistry.1a In the
sole reported attempt at the synthesis of composite knots for more
than 20 years,5a Sauvage ’ s group carried out the
cyclodimerization of linear Cu(I) helicates. However, there was
no attempt to control stereochemistry and the result was an
inseparable mixture of granny and square knots, together with
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topologically-trivial macrocycles.5a Recently, symmetrical
be safely removed without the entanglement being able to
unravel.
Accordingly, we decided to use lanthanide-coordinated
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interwoven grids5b,7 and circular helicates5c have been used to
control the relative stereochemistry of strand crossings in the
synthesis of a granny knot and a nine-crossing composite knot.5b,5c
However, those strategies did not control absolute stereochemistry
(chirality) either, nor are these approaches readily extendable to
topologies with less symmetrical crossing patterns.1a,f
overhand knots as entanglement synthons to selectively construct
composite knots with different stereochemistries. A CuAAC
coupling step followed by ring closing metathesis (RCM) was
used to combine two overhand knots to form open-ended and
closed-loop six-crossing strands of precise stereochemical
composition.12 The approach was exemplified through the
stereoselective synthesis of a topologically achiral square knot,
Λ,Δ-1, and the enantioselective synthesis of granny knots Λ,Λ-1
and Δ,Δ-1 (Figure 2).
Given the stereochemical parallels between asymmetric centers
and strand crossings, we wondered whether strategies used in
conventional asymmetric synthesis could be usefully applied to
the stereoselective synthesis of different molecular knot
9
topologies. The ‘chiron approach
’8 is a simple but effective
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approach for constructing molecules with multiple asymmetric
centers. Minimalist chiral synthons, usually derived from cheap
and readily available natural products, are combined to form the
target molecule stereoselectively. However, a complication in
trying to extend such an approach from asymmetric centers to
strand entanglements is that although most asymmetric carbon
RESULTS AND DISCUSSION
Suitable ligand strands containing a terminal alkene at one end
of the tris(2,6-pyridinedicarboxamide) strand and either alkyne
(L1) or azide (L2) groups at the other, were prepared as outlined
in the Supporting Information. The lengths of the spacers linking
the alkene, alkyne and azide groups to the rest of the strand
proved important for achieving efficient macrocyclization to the
closed-loop composite knots.13 Each synthon was treated with
Lu(CF3SO3)3 in MeCN at 80 °C to generate the corresponding
overhand knots, Λ-L1•[Lu], Δ-L1•[Lu], Λ-L2•[Lu] and Δ-
L2•[Lu] in 73-85 % yields. In all cases the folding-threading
process to form the overhand knot was found to be complete after
16 h, as evidenced by electrospray ionization mass spectrometry
(ESI-MS, Figures S4 and S5) and 1H NMR spectroscopy (Spectra
S19-S22). Signals diagnostic of the entangled conformations of
the L1•[Lu] and L2•[Lu] complexes include large upfield shifts of
the pyridine Hb1,b2 protons due to their proximity to aromatic rings
in the overhand knots. The handedness of the entanglements,
dictated by point chirality in the ligand strands, was confirmed by
circular dichroism (Spectrum S34).
atoms are configurationally fixed, an entanglement is
a
conformation that can be undone by bond rotations in a strand
with open ends.
It
has
previously
been
shown
that
tris(2,6-
pyridinedicarboxamide) ligands can be tied into overhand
knots5a,9 (three-crossing entanglements or ‘trefoil tangles ’) upon
coordination to lanthanide(III) ions.10 The handedness of the
entanglement can be controlled by introducing asymmetry at the
benzylic positions of the ligand backbone: sterics dictate that only
the Λ-overhand knot conformation forms from the (R,R,R,R,R,R)-
strand while the (S,S,S,S,S,S)-enantiomer generates the Δ-
overhand knot (Figure 2).11 Crucially, as long as a lanthanide ion
remains coordinated, the strand entanglement remains in place
with its handedness retained. This makes the coordinated unit a
potential ‘entanglement synthon ’ with open ends for constructing
knots by adding together crossings. Once a linear combination of
such synthons is macrocyclized to form a closed loop the crossing
sequence will become topologically fixed and the metal ions can
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b1
b2
1
2
3
4
O
O
O
O
O
O
N
N
N
a1
a2
a3
a4 a5
a6
NH
HN
NH
NH
HN
HN
*
*
*
*
*
*
5
6
7
8
9
O
O
d
O
O
O
O
O
O
O
OR
e
L1
L2
R =
R =
O
(i)
f
3
c
h
N3
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g
3+
3 CF3SO3
3+
3 CF3SO3
-
-
O
O
3


3
R
R
O
O
= 6 x (S)
= 6 x (R)
O
O
*
*
H
H
N
H
N
H
N
N
N
N
O
O
O
O
O
O
O
N
NH
O
NH
N
HN
Lu
Lu
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
NH
N
H
HN
NH
O
O
O
O
N3
N3
L1•
L2•
L1•
L2•
-
[Lu]
-
[Lu]
-
[Lu]
-
[Lu]
Figure 2. Lanthanide coordination induces folding and threading of L1/L2 to form entanglement synthons: alkene and alkyne- or azide-
bearing overhand knots of single handedness (Λ or Δ). Reagents and conditions: (i) Lu(CF3SO3)3, MeCN, 80 °C, 16 h. Yields: 81% (Λ-
L1•[Lu]), 82% (Δ-L1•[Lu]), 85% (Λ-L2•[Lu]), 73% (Δ-L2•[Lu]).
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contain products resulting from incomplete olefin metathesis and
1
2
3
the presence of other anions (1H NMR analysis of the reaction
mixture indicates that olefin metathesis proceeds in ~80 %
conversion per alkene).
The closed-loop structure of (Λ,Δ)-1•[Lu]2 was confirmed by
1H NMR spectroscopy (e.g. loss of terminal alkene protons Hd;
Figure 3b), ESI-MS (molecular ion mass corresponds to loss of
C2H4, Figure 3a) and high resolution mass spectrometry (HR-MS;
the isotope distribution of the molecular ion confirming the
molecular formula, Figure 3a inset). Diffusion ordered
spectroscopy (DOSY) shows that the composite knots diffuse
with a larger hydrodynamic radius than the overhand knot
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Scheme 1. Synthesis of double overhand knot (Λ,Δ)-
L3•[Lu]2 and square knot (Λ,Δ)-1.
N3
+
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6+
O
O
-
6 CF SO building block, Λ-L1•[Lu] (Spectra S1 and S2).
3
3
O
O
 L1•
-
[Lu]
 L2•
-
[Lu]
O
O
O
i
O
HN
O
NH
O
N
NH
O
O
HN
N
O
O
HN
N
N
O
O
NH
O
Lu
N
N
O
O
O
O
3
HN
O
Lu
N
O
N
NH
O
NH
3
O
N
O
HN
HN
O
NH
O
O
O

L3•
-
[Lu]2
O
O
O
O
6+
6 CF3SO3
O
O
-
O
O
ii
O
O
O
O
O
HN
NH
O
N
NH
O
O
HN
N
O
HN
N
N
O
O
NH
O
Lu
N
N
O
O
O
3
HN
O
O
Lu
O
N
O
N
NH
O
NH
O
N
O
3
HN
O
HN
NH
O
O
O

1
- •[Lu]2
O
O
O
O
iii
Square knot

1
-
Reagents and conditions: (i) Cu(MeCN)4(CF3SO3), Tentagel-
TBTA, MeCN/MeOH 1:1, RT, 16 h, 70 %. (ii) Hoveyda-Grubbs
2nd generation catalyst, MeNO2/CH2Cl2 1:1, 30 %. (iii) Et4NF,
MeCN, RT, 5 min, 95 %.
To generate the square knot, Λ-L1•[Lu] was first connected to
Δ-L2•[Lu] through a CuAAC reaction, giving the double
overhand knot (Λ,Δ)-L3•[Lu]2 in 70% yield after purification by
size exclusion chromatography (Scheme 1). 1H NMR
spectroscopy showed the absence of an alkyne proton Hf at ~3.0
ppm, together with shifts in the resonances corresponding to the
azide α-protons Hh (3.65-4.81 ppm) and β-protons Hg (2.19-2.53
ppm), and the propargylic α-protons He (3.94-4.98 ppm) (Figure
3b, i-iii).
Figure 3. (a) ESI-MS (positive mode) of square knot complex
(Λ,Δ)-1•[Lu]2 (inset: isotopic distribution from HR-MS). (b)
Partial 1H NMR spectra (600 MHz, MeCN-d3, 298 K) of (i)
entanglement synthon Δ-L2•[Lu], (ii) entanglement synthon Λ-
L1•[Lu], (iii) double overhand knot (Λ,Δ)-L3•[Lu]2, (iv) square
knot coordination complex (Λ,Δ)-1•[Lu]2. For full assignments,
see the Supporting Information.
Macrocyclization of (Λ,Δ)-L3•[Lu]2 occurred over 14 hours at
50 °C in a MeNO2/CH2Cl2 (1:1) solvent mixture using the 2nd
generation Hoveyda-Grubbs catalyst.14 After work-up, size
exclusion chromatography afforded the metallated molecular
square knot, (Λ,Δ)-1•[Lu]2, in 30 % yield. The isolated pure
material is only a fraction of the amount actually formed. The
closed knot is difficult to separate from closely running bands that
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Coordination
complex
(Λ,Δ)-1•[Lu]2
was
smoothly
1
2
3
4
5
6
7
demetallated with tetraethylammonium fluoride in MeCN,
affording the metal-free square knot (Λ,Δ)-1 in 95 % yield within
5 minutes at RT (Supporting Information Section 4.2). In line
1
with other complex intertwined organic compounds,4d,e,5b,c the H
NMR of (Λ,Δ)-1 is broad (Figure S2), presumably due to
conformational dynamics of the strand (e.g. reptation15) being
significantly impeded by the entanglement. Slight sharpening of
1
the H NMR spectrum occurs at elevated temperatures (Spectrum
S34). This may be a result of the loosening of intra-strand amide-
amide hydrogen bonding as well as increased reptation.
Remetallation of the wholly organic knot could be accomplished
through treatment with excess lutetium trifluoromethanesulfonate
(MeCN, 80 °C, 18 h; Figure S3).
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Enantioselective syntheses of each enantiomer of the granny
composite knot were achieved in a similar fashion to the square
knot (Figure 4). Starting from the three-crossing entanglement
synthons with Λ-handedness, Λ-L1•[Lu] and Λ-L2•[Lu], granny
knot (Λ,Λ)-1•[Lu]2 was isolated in 26 % yield over two steps
(Figure 4a). Its enantiomer (Δ,Δ)-1•[Lu]2 was synthesized from
the two Δ-entanglement synthons in 16 % overall yield (Figure
4b). The identity of each composite knot was confirmed by NMR
spectroscopy and HR-MS. Demetallation of the granny knot
(Λ,Λ)-1•[Lu]2, under similar conditions to those used for the
square knot, afforded (Λ,Λ)-1 in 92 % yield (Supporting
Information Section 4.2), with no appreciable difference in rate
between the two topoisomers. The topology-based stereochemical
differences between (Λ,Λ)-1 and (Λ,Δ)-1 are insufficient to
significantly influence the reactivity of the labile lanthanide-
ligand interactions.
The 1H and 13C NMR spectra of the granny and square knot are
essentially indistinguishable (Spectra S27-S30). However, the
composite knot diastereomers differ significantly in circular
dichroism measurements (Figure 5). The CD spectra of the
lanthanide complexes of the granny knot enantiomers (Λ,Λ)-1 and
(Δ,Δ)-1 are symmetrical in terms of curve shape and have exciton
couplings of equal and opposite sign with maxima at 253 nm,
demonstrating the chirality (of opposite handedness) of their
structures.16 The exciton couplets are consistent with the absolute
configuration of the entanglement helicities of the synthons.10 The
CD response of the square knot coordination complex is virtually,
but not quite, baseline (Figure 5, green trace). The very small
Cotton effect likely stems from the triazole ring in the composite
knot strand connecting to the two entanglement synthons in non-
identical ways: through a carbon atom of what was the alkyne
group in Λ-L1•[Lu] and a nitrogen atom of what was the azide
group in Δ-L2•[Lu]. The resulting break in the symmetry in the
chemical constitution of the knot strand results in the molecule
not having a perfect plane of symmetry between its two halves:
The square knot prepared from Λ-L1•[Lu] and Δ-L2•[Lu] would
not be superimposable on one prepared from the enantiomeric
building blocks, Δ-L1•[Lu] and Λ-L2•[Lu]. Although (Λ,Δ)-1 is
topologically achiral, because of the chemical make up of the
strand it is not a true meso-compound. Accordingly, its lanthanide
complex elicits a very small, but finite, CD response.
Figure 4. (a) Synthesis and HR-MS of granny knot complex
(Λ,Λ)-1•[Lu]2. Conditions: (i) Cu(MeCN)4(CF3SO3), Tentagel-
TBTA, MeCN/MeOH 1:1, RT, 16 h, 79 %. (ii) Hoveyda-Grubbs
2nd generation catalyst, MeNO2/CH2Cl2 1:1, 33 %. (b) Synthesis
and HR-MS of granny knot complex (Δ,Δ)-1•[Lu]2. Conditions:
(iii) Cu(MeCN)4(CF3SO3), Tentagel-TBTA, MeCN/MeOH 1:1,
RT, 16 h, 52 %. (iv) Hoveyda-Grubbs 2nd Gen, MeNO2/CH2Cl2
1:1, 31 %. For each of the ion isotopic distributions, the
experimentally observed spectrum is shown above the
theoretically calculated spectrum.
Figure 5. Circular dichroism spectra (1.0×10−4 M, MeCN, 298
K) of granny knots (Λ,Λ)-1•[Lu]2 (blue) and (Δ,Δ)-1•[Lu]2 (red)
and square knot (Λ,Δ)-1•[Lu]2 (green). Normalized for
absorbance.
CONCLUSIONS
Three molecular six-crossing composite knots of different
topologies, -31#-31 (granny), +31#+31 (granny) and +31#-31
(square), were synthesized stereoselectively through a strategy
involving joining together entanglement synthons of particular
handedness to form a linear strand with multiple tangles that are
each held in place by coordination to lanthanide cations.
Subsequent macrocyclization of each strand locks its topology,
forming a closed loop, 199 atoms long, from which the metal ions
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(2) (a) Dietrich-Buchecker, C. O.; Sauvage, J.-P. A synthetic molecular
can be removed without the knot being able to unravel. Tris(2,6-
pyridinedicarboxamide) ligands were shown to be suitable 31
entanglement synthons of either handedness (chirality
predetermined by choice of asymmetric centers on the ligand
strand). The resulting granny knots are enantiomers (each with six
alternating crossings) that exhibit pronounced equal and opposite
CD spectra. The diastereomeric square knot is topologically
achiral (two non-alternating crossings and four alternating
crossings), but a lack of symmetry in the chemical constitution of
the knot strand means this example is not a true meso-compound.
The synthetic strategy is related to both the chiron approach8 of
conventional asymmetric synthesis and tangle theory,1a,3 a way
that mathematicians understand and (de)construct complex knot
topologies through simpler fragments termed ‘tangles’. The new
approach may prove useful for the preparation of other complex
molecular knots and entangled materials that lack high symmetry
in their crossing patterns.
trefoil knot. Angew. Chem., Int. Ed. Engl. 1989, 28, 189–192. (b) Ashton,
P. R.; Matthews, O. A.; Menzer, S.; Raymo, F. M.; Spencer, N.; Stoddart,
J. F.; Williams, D. J. A template-directed synthesis of a molecular trefoil
knot. Liebigs Ann. Chem. 1997, 2485–2494. (c) Dietrich-Buchecker, C.
O.; Hwang, N. G.; Sauvage, J.-P. A trefoil knot coordinated to two lithium
ions: synthesis and structure. New J. Chem. 1999, 23, 911–914. (d)
Safarowsky, O.; Nieger, M.; Fröhlich, R.; Vögtle, F. A molecular knot
with twelve amide groups—one-step synthesis, crystal structure, chirality.
Angew. Chem. Int. Ed. 2000, 39, 1616−1618. (e) Feigel, M.; Ladberg, R.;
Engels, S.; Herbst-Irmer, R.; Fröhlich, R. A trefoil knot made of amino
acids and steroids. Angew. Chem. Int. Ed. 2006, 45, 5698−5702. (f) Guo,
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI. Synthetic procedures and
NMR, MS, CD, UV/Vis data and molecular models (PDF).
AUTHOR INFORMATION
Corresponding Author
Correspondence to: david.leigh@manchester.ac.uk
Notes
The authors declare no competing financial interests.
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molecular level. Proc. Natl. Acad. Sci. USA, published online 25 Jan 2019.
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A Six-Crossing Doubly Interlocked [2]Catenane with Twisted Rings, and
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of a composite knot with nine crossings. Nat. Chem. 2018, 10, 1083–1088.
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ACKNOWLEDGMENT
We thank the Engineering and Physical Sciences Research
Council (EPSRC; EP/P027067/1), the EU (Marie Curie Individual
Postdoctoral Fellowship to FS; EC 746993) and the School of
Chemistry Mass Spectrometry Service Centre for high-resolution
mass spectrometry. We are grateful to Guzman Gil-Ramírez and
Gen Zhang for preliminary studies on this general concept, David
August for assistance with the DOSY experiments and Joakim
Halldin Stenlid for modeling studies. DAL is a Royal Society
Research Professor.
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(12) In preliminary studies we were unable to find spacers of a length
and conformation that tolerated the one-step combination of entanglement
synthons to form composite knots (e.g. dimerization of an entangled bis-
alkene to form a granny knot; or combination of an entangled bis-azide
and bis-alkyne of different handedness to form a square knot).
(13) Molecular modeling indicates that a double overhand knot such as
(Λ,Δ)-L3•[Lu]2 adopts a conformation that places the reactive endgroups a
relatively long distance away from each other, hence the use of relatively
short spacers to the azide and alkyne for the CuAAC step that couples the
synthons and relatively long and flexible chains for the subsequent RCM
ring closure (see Figure S11).
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(11) (a) Zhang, G.; Gil-Ramírez, G.; Markevicius, A.; Browne, C.;
Vitorica-Yrezabal, I. J.; Leigh, D. A. Lanthanide template synthesis of
trefoil knots of single handedness. J. Am. Chem. Soc. 2015, 137, 10437–
10442. See also: (b) Kotova, O.; Kitchen, J. A.; Lincheneau, C.; Peacock,
R. D.; Gunnlaugsson, T. Probing the effects of ligand isomerism in chiral
(16) There is a small difference in intensity of the CD responses
recorded for the two isolated granny knots when the spectra are
normalized for UV-absorbance (Figure 5). This likely results from a trace
impurity in ( Δ, Δ)-1. No epimerization of asymmetric centers occurs
during any of the synthetic steps (the resulting diastereomers are
luminescent lanthanide supramolecular self‐assemblies:
a Europium
“Trinity sliotar” study. Chem. Eur. J. 2013, 19, 16181–16186. (c) Kitchen,
J. A. Lanthanide-based self-assemblies of 2,6-pyridyldicarboxamide
ligands: Recent advances and applications as next-generation luminescent
and magnetic materials. Coord. Chem. Rev. 2017, 340, 232–246. (d)
Barry, D. E.; Caffrey, D. F.; Gunnlaugsson, T. Lanthanide-directed
synthesis of luminescent self-assembly supramolecular structures and
1
detectable by H NMR10a,11a) and folding to an entanglement of opposite
handedness is not possible on steric grounds for any of the lanthanide-
coordinated overhand knot intermediates10a,11a
.
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