Synthesis of a D3-symmetric "trefoil" knotted cyclophane

Article abstract of DOI:10.1039/c1cc11209k

A D₃-symmetric knotted cyclophane, with a subgraph of trefoil topology, was synthesized by cyclization of a D₃-symmetric scaffold. Control of configuration at the three metal-based stereocenters arises from a bascule/pivot mechanism. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc11209k

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Chemical Communications
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Volume 47 | Number 34 | 14 September 2011 | Pages 9533–9736
ISSN 1359-7345
COMMUNICATION
Jay S. Siegel et al.
Synthesis of a D3-symmetric “trefoil”
knotted cyclophane
1359-7345(2011)47:34;1-B

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COMMUNICATION
Synthesis of a D3-symmetric ‘‘trefoil’’ knotted cyclophanew
Karla I. Arias,a Eli Zysman-Colman,b Jon C. Loren,c Anthony Lindena and Jay S. Siegel*a
Received 28th February 2011, Accepted 4th May 2011
DOI: 10.1039/c1cc11209k
A D3-symmetric knotted cyclophane, with a subgraph of trefoil
topology, was synthesized by cyclization of a D3-symmetric
scaffold. Control of configuration at the three metal-based
stereocenters arises from a bascule/pivot mechanism.
configuration of the metal-coordinating stereocenters, a
template was designed comprising three bis-bipyridylphenyl
pivot arms centrally connected via alkyne spacers to a rigid
benzene core.
Initial coordination of a metal ion, like CuI, by ligands
of neighboring pivot arms sets the configuration about the
metal-centered stereocenter and then a cantilever mechanism
dictates the overall configuration at the remaining metal-based
stereocenters; when one side of the pivot arm moves down to
coordinate to a metal, the other moves up. The result is the
formation of a D3-symmetric complex.10
Complex topologies sophisticate life’s macromolecules,
provoke molecular architects and challenge stereochemical
theory.1,2 From Byzantine biopolymers3 to concatenated
coordination complexes,4 these purely mathematical constructs
find empircial expression as effigies of valence-bond-encoded
molecular graphs. The taxonomy of topological stereochemistry
focuses on three fundamental classes: links, knots and
‘‘non-planar’’ graphs.5 Each structure requires an entwinement
wherein entropy disfavors a stochastic selection. The most
successful synthetic strategies toward topological targets
employ templating effects like metal coordination,6,7 charge-
transfer stacking,8 and hydrogen-bonding templates,9 each
of which has led to trefoil knotted molecules of various
symmetries. A metal-directed approach via a D3-symmetrical
scaffold offers a strategy to a D3-symmetrical knotted cyclophane
with high stereoselectivity.
Synthesis of 12 results from a manifold use of palladium-
catalyzed cross-coupling reactions (Scheme 1). Bipyridine 4
comes via two successive Negishi couplings.11 Palladium catalyzed
conversion of 4 to stannane 5 proceeds in excellent yield, albeit
with stoichiometric amounts of hexamethylditin.12 Two
equivalents of 5 couple well to dibromophenyltriazine 6 under
optimized Stille conditions, to form 7, which precipitates out of
The retrosynthesis of the knotted cyclophane is easily
visualized (Fig. 1). Key challenges include: (a) configurational
(over–under) control of the metal-based stereocenters,
(b) construction of the crescent-shaped pivot arms, and (c)
installation of the peripheral linkers capable of closing the
circuit and completing the knotted architecture. To control the
Fig.
1
Schematic retrosynthesis of a D3-symmetrical knotted
cyclophane.
Scheme 1 Synthesis of 12: (a) 1. nBuLi/THF, À78 1C, 40 min, 2. ZnCl2/
THF, À78–0 1C, 1 h, 3. 1 equiv. 2,6-dibromopyridine, 1.5 mol%
Pd(PPh3)4/THF, reflux, 18 h [83%]; (b) 1. nBuLi/THF, À78 1C,
40 min, 2. ZnCl2/THF, À78–0 1C, 1 h, 3. 1 equiv. 2,5-dibromopyridine,
1.5 mol% Pd(PPh3)4/THF, reflux, 18 h [48%]; (c) (SnMe3)2, 2 mol%
Pd(PPh3)4/DME, reflux, 5.5 h [92%]; (d) 0.5 equiv. 6, 10 mol%
Pd(PPh3)4/toluene, reflux, 18 h [83%]; (e) 2 equiv. I2/ClCH2CH2Cl,
reflux, 48 h [96%]; (f) 47% HI (aq.), reflux, 16 h, // 3 equiv. TIPSOTf/
CH2Cl2, NEt3, À78–0 1C, 14 h [88%]; (g) 0.3 equiv. 10, 10 mol%
Pd(PPh3)4/1 : 1 NEt3 : toluene, reflux, 18 h [70%]; (h) 1. 6.6 equiv.
TBAF/THF, À78 1C—RT, 4 h, 2. 6.6 equiv. pent-4-ynyl toluenesulfonate,
20 equiv. Cs2CO3/DMF, 85 1C, 18 h [95%].
a Organisch-chemisches Institut, Universitat Zurich,
Winterthurerstrasse 190, 8057, Zurich, Switzerland.
¨
¨
¨
E-mail: jss@oci.uzh.ch; Fax: +41 44-635-6888
´
b
´
Faculte des Sciences, Universite de Sherbrooke,
´
2500 Blvd de l’Universite, Sherbrooke J1K 2R1, Canada
c Dept of Medicinal Chemistry, The Genomics Institute of the Novartis
Research Foundation, 10675 John Jay Hopkins Dr, San Diego,
CA 92121, USA
w Electronic supplementary information (ESI) available: 67 Pages of
procedures, data and spectra. CCDC 779280. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c1cc11209k
c
9588 Chem. Commun., 2011, 47, 9588–9590
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Fig. 2 UV/Vis spectral titration of CuI(MeCN)4PF6 with 12 in
CH2Cl2. Inset: Job Plot for CuI(MeCN)4PF6 vs. 12 at 450 nm in
CH2Cl2.
solution.13 After filtration, crescent
7 is converted to
Scheme 2 Synthesis of 1. (i) 3 equiv. CuI(MeCN)4PF6/1 : 1 NEt3 :
CH2Cl2, RT, 2 h [95%]; (j) 36 equiv. CuII(OAc)2ÁH2O/CH3CN, reflux,
16 h [85%]; (k) 20% KCN (aq.)/CH2Cl2, RT, 2 h [91%].
the corresponding iodo-crescent (8) with iodine in refluxing
1,2-dichloroethane.14
Manisyl groups improved the solubility compared to anisyl
groups, making it easier to work with 8–12.15 Deprotection of
8 in refluxing 47% HI (aq) and subsequent reprotection as the
triisopropylsilyl (TIPS) ether formed 9 (two steps). Copper-free
Sonogashira coupling of 9 with 10 (3 equiv.) afforded 11,16 and
in situ desilylation/alkylation of 11 crafted 12 [9 steps, 17%
yield].17
A Job plot of mole fraction 12 vs. CuI(MeCN)4PF6 at
450 nm displays a sharp maximum at a CuI : 12 molar ratio
of 3 : 1, supporting one CuI per site (Fig. 2). Such a sharp
maximum suggests strong binding in favor of the 3 : 1
complex; however, titration of 12 with CuI(MeCN)4PF6 does
not show clean isosbestic behavior. With the addition of up to
1.5 equiv. of CuI to 12, the absorption curves share isosbestic
points at 260, 281, and 315 nm. From 2 to 2.5 equiv. of CuI,
the absorption curves share isosbestic points at 256, 277, 300,
and 359 nm. Beyond 3 equiv. of CuI, the curves are constant.
This behavior suggests the presence of at least two intermediate
bound states in solution.18 The values of the stability and
formation constants of the tri CuI complex were determined
from the UV/Vis spectra (Table 1),19 and indicate that the
formation of 13 from CuI and 12 is at best weakly cooperative.
Treatment of 13 with excess CuII(OAc)2ÁH2O in refluxing
CH3CN20 results in the formation of knotted cyclophane 14 in
excellent yield (Scheme 2). Formation of the desired product
was deduced from ESIMS data, plus the loss of the terminal
Fig. 3 600 MHz 1H NMR of 13 (red) and 14 (blue) in CD2Cl2.
(ref. 5.32 ppm from CHDCl2). Inset: IR of 13 (red) and 14 (blue).
Black arrows indicate the terminal alkyne signal in 13.
1
alkyne signals in both the IR and H NMR spectra. (Fig. 3).
Dark red crystals were grown from vapor diffusion of ether
into a nitromethane solution of the hexafluorophosphate salt
of 14; crystal structure determination unequivocally confirmed
the formation of the desired knotted structure, which possesses
the correct topology and connectivity (Fig. 4).21 The formally
Fig. 4 Crystal structure of 14: (left) spacefilling; (right) capped-stick.
D3 knotted cyclophane 14 packs with crystallographic C3
symmetry. It displays three CuI centers at the vertices of an
equilateral triangle of edge length ca. 10.9 A. Further analysis
of the crystal structure reveals that the knotted copper-
complexed cyclophane crystallizes as a racemate within a cubic
Table 1 Stability constants of CuI(MeCN)4PF6 into 12
log K1
log K2
log K3
log b2
log b3
6.54(0)
4.33(9)
5.50(0)
10.88(0)
16.38(2)
crystal system (space group: Pꢀ43n). Synthesis of knotted metal-
Calculated using ReactLab Equilibria from UV/Vis spectra in
CH2Cl2.
free cyclophane 1 was achieved by the removal of the copper
with an aqueous solution of KCN (c.f. Scheme 2).
c
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Chem. Commun., 2011, 47, 9588–9590 9589

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Table 2 Absorption and emission maxima, molar absorptivity values
(log e), quantum yields (ff), and lifetimes (tf)
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UV/Visa
abs/nm
Fluorescenceab
l
log e/cmÀ1 molÀ1
L
l
em/nm
ff
tf/ns
15
16
12
1
283
310
297
293
4.19
4.73
5.15
5.03
370
372
375
373
0.04
0.08
0.31
0.20
1.63
2.58
2.79
3.02
a
b
All values measured in CH2Cl2. PPO in cyclohexane (ff = 0.94)
was the standard;22 the emission maxima values were obtained at 75%
height.
The photophysical properties of reference compounds 15,
16 and 12 showed an increase in the molar absorptivity,
quantum yield, and lifetime in CH2Cl2 across the series. The
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Synthesis of a D3-symmetric knotted cyclophane was
achieved by the cyclization of the alkynyl-capped intermediate
12 using the Eglinton protocol. The desired over–under
arrangement is controlled by means of a cantilever mechanism
to complex CuI ions to the crossed polypyridine arm in
12 - 13. Completion of the trefoil knot synthesis still requires
the cleavage of the central triethynylbenzene scaffold.
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3040.5, cubic, a = 33.7312(6) A, V = 38379(1) A3, T = 160(1)
K, space group P43n
ꢀ
, Z = 8, m(Mo-Ka) = 0.420 mmÀ1, 153 129
reflections measured, 7819 unique reflections, 4112 reflections with
I 4 2s(I). The available crystals were of poor quality and were
possibly not true single crystals. The best refinement yielded
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9590 Chem. Commun., 2011, 47, 9588–9590
This journal is The Royal Society of Chemistry 2011