The thread & cut method: Syntheses of molecular knot precursors

Article abstract of DOI:10.1002/ejoc.200800387

A novel approach to molecular knots is described. This method may allow access to smaller and more complex knots. Two knot precursors, 1a and 1b, are efficiently prepared in overall yields of 9.6% and 8.7%, respectively. The convergent six-step syntheses utilize Frechet-type etherifications, alkyne/azide click cycloadditions, and bis-macrolactonizations. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800387

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800387
The Thread & Cut Method: Syntheses of Molecular Knot Precursors
Edward E. Fenlon*[a] and Brandon R. Ito[a]
Dedicated to Professor Steven C. Zimmerman on the occasion of his 50th birthday
Keywords: Chemical Topology / Chirality / Macrocycles / Molecular knots / Synthesis design
A novel approach to molecular knots is described. This
method may allow access to smaller and more complex
knots. Two knot precursors, 1a and 1b, are efficiently pre-
pared in overall yields of 9.6% and 8.7%, respectively. The
convergent six-step syntheses utilize Fréchet-type etherifi-
cations, alkyne/azide click cycloadditions, and bis-macrolac-
tonizations.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
There have been many notable achievements in chemical
topology,[1,2] including the syntheses of molecular trefoil[3]
and composite knots,[4] Solomon[5] and Borromean links,[6]
and a Möbius strip.[7] In the DNA realm,[8] more complex
topologies have been achieved, including the figure eight[9]
and endless knots.[10] Proteins also form knots,[11] but many
of these are not closed loops, so topologically they are not
true knots.[12]
In the field of small-molecule topology, many open prob-
lems remain. Principal among these are: 1) what is the
smallest knot that can be prepared? and 2) can prime knots
more complex than the trefoil be prepared? Addressing
these questions may help the development of new nanotech-
nologies.
Regarding the smallest knot that can still physically
form, Wasserman used models to predict that a polyethyl-
ene trefoil requires at least 50 backbone atoms.[1] More re-
cent calculations, however, suggested that the stability
boundary for this knot may be 43 atoms or fewer.[13] The
smallest known knot is an 80-atom trefoil prepared by
Sauvage.[14] In terms of complexity, if one discounts DNA
knots, the only prime knots to be deliberately prepared in
molecular form are the unknot and trefoil (Figure 1). Syn-
thetic efforts and strategies toward the next two prime
knots, the figure eight[16] and pentafoil,[17] have been pub-
lished, but these targets remain elusive.
Figure 1. The first eight prime knots: unknot (01), trefoil (31), figure
eight (41), pentafoil (51), three twist (52), and the six-crossing knots
(61, 62, 63). The unknot and trefoil are the only non-DNA molecu-
lar examples deliberately synthesized. Billions of prime knots have
been catalogued by mathematicians.[15]
Results and Discussion
Our thread & cut strategy[18] may allow smaller and more
complex knots (i.e., the figure eight) to be prepared. The
approach centers around knot precursor 1, which is com-
posed of two macrocycles and two tails (Figure 2). Key fea-
tures of 1 include: 1) a fluorescent 2,5-dihydroxytereph-
thalic acid core[19] (blue ring) that exhibits an intense blue
color under UV irradiation (λmax = 334 nm); 2) a highly
efficient and convergent synthetic route (vide infra) that em-
ploys etherifications (alkylations of green and blue rings)
and an alkyne/azide click cycloaddition[20] to yield triazoles
(red rings); 3) the ability to adjust the size of the knots
produced simply by varying the length of linker 1, linker 2,
or the tail; 4) robust functionality, except for purposely la-
bile esters; and 5) the fact that only one bond is formed
in the proposed knot-tying step, producing only isomeric
products, not homologues as with other strategies.
[a] Department of Chemistry, Franklin & Marshall College,
P. O. Box 3003, Lancaster, PA 17601, USA
The proposed knot-tying step is a ring-closing olefin me-
tathesis[21] (RCM) of 1 under high dilution, during which
threading of the tails through the macrocycles can occur.
E-mail: efenlon@fandm.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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E. E. Fenlon, B. R. Ito
SHORT COMMUNICATION
and ropes[28] is spontaneous, conducting the RCM in a sol-
vent in which 1 has low solubility, should give rise to solvo-
phobic interactions which may in turn promote threading
and increase the probability of knotting.
The synthetic routes commence with Fréchet-type etheri-
fications. Alkylation of 3,5-dihydroxybenzyl alcohol (2)
with one equivalent of mesylate 3 provided the alkyne 4 in
good yield (42%), considering the symmetry of 2 is broken
(Scheme 1). A second etherification with the bromide 5a or
the mesylate 5b provided the eneynes 6 in modest yields.
Figure 2. Chemical and schematic (inset) structures of the general-
ized form of molecular knot precursor 1. The length of linkers and
tails can be varied to place constraints on the RCM knot-tying
step. The scissors indicate the ester bond to be hydrolyzed (cut)
after the knot-tying step, see text and Table 1.
After the RCM, the labile ester bonds are hydrolyzed (cut)
to give the knot products. In this system, productive thread-
ing occurs when a tail threads through the opposing macro-
cycle;[22] e.g., tail a threads through macrocycle B (Figure 2,
Table 1). The meta isomers[19] of knot precursors 1a and 1b
(Scheme 2) each contain two 27-atom macrocycles. Com-
pound 1a has shorter tails (13 atoms) and CPK models sug-
gest that steric constraints limit intramolecular products to
the unknot and trefoil (Table 1). The trefoil would result if
tail a threads top-down through macrocycle B and tail b
threads top-down through macrocycle A followed by RCM
and ester cleavage. The enantiomeric trefoil results if both
threading events occur in a bottom-up manner. In 1a the
tails are too short to reach each other if they thread from
opposite sides. CPK models suggest that the longer 22-atom
tails of 1b do permit RCM after threading from opposite
sides of the macrocycle. This latter mode of threading
would result in the figure eight knot after RCM and ester
cleavage (Table 1). This knot is a particularly attractive tar-
get because of its unusual stereochemistry – it is a topologi-
cal rubber glove.[23,24] This term, first introduced by
Walba,[23] denotes a compound that contains no rigidly
achiral representation but has a chiral enantiomerization
pathway making it topologically achiral.[25,26]
Scheme 1. Syntheses of the eneynes 6.
Preparation of the diazide 9 proceeded smoothly upon
etherification of diethyl 2,5-dihydroxyterephthalate (7) with
the bromide 8 (Scheme 2). A copper-catalyzed alkyne/azide
click cycloaddition of 6 and 9 provided the bis-triazoles 10
in moderate yields. The IR spectra of 10 lacked the alkyne
(2118 cm–1) and azide (2093 cm–1) absorptions of 6 and 9,
1
respectively, and the H NMR spectra showed a new aro-
matic resonance (δ = 7.33 ppm) for the triazole rings. Sa-
ponification of 10 provided the diacids 11 in quantitative
yields. Finally, the knot precursors 1 were furnished in mod-
erate to good yields via bis-macrolactonization of 11 using
Shiina’s mixed-anhydride method under high dilution.[29]
Evidence for the structure of 1 includes the downfield shift
of the benzylic protons in the 1H NMR spectra by ca.
0.66 ppm, in agreement with ester formation. The electro-
spray mass spectra also support the structures with molecu-
lar ions at 1297.9 and 1555.2 Da for 1a and 1b, respectively.
Furthermore, for the first time in the syntheses, the NMR
spectra of the purified products indicated a mixture of two
isomers, as expected. Integration of the benzylic proton
peaks indicated a 64:36 isomer ratio for 1a and a nearly
identical ratio for 1b. The isomers proved to be inseparable
and it is unknown whether the ortho or meta isomer is the
major product.[19]
Table 1. Representative thread & cut outcomes for proposed RCM-
ester hydroylsis reactions of knot precursors 1.
Preliminary experiments on the thread & cut sequence
have produced noteworthy results. For example, RCM of 1b
with Grubb’s first generation catalyst (10–4  in acetone)
The preorganization of 1 should aid knot formation; e.g., followed by ester hydrolysis produced two products. Prepa-
RCM of 1a only requires formation of a 42-atom macro- ratory TLC purification gave 3.8 mg (2.5%, two steps) of
cycle from which, after cutting, a 72-atom trefoil results. the less polar product and 6.3 mg (4.5%, two steps) of the
Furthermore, even though knot formation in polymers[27] more polar product. Negative ion electrospray mass spec-
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Syntheses of Molecular Knot Precursors
yields of 9.6% and 8.7%, respectively. Preliminary results
on the RCM/ester hydrolysis sequence suggest that this
strategy may afford products with non-trivial topologies.
The method may allow access to smaller knots; e.g., precur-
sor 1a would produce a 72-atom trefoil, 10% smaller than
the current record.[14] The knot precursor 1b may allow ac-
cess to a figure eight knot. A non-DNA version of this knot
would be the first example of a chemically achiral molecu-
lar knot that is also a topological rubber glove.[23,24] Further
characterization of the products from the thread & cut ex-
periments are ongoing and will be reported in due course.
Meanwhile, second-generation iterations of the method are
also being pursued. These systems encourage tail threading
by employing more rigid macrocycles, which should main-
tain an open conformation, and incorporation of molecular
recognition elements between the tail and the macrocycle.
Experimental Section
Diethyl 2,5-Bis(4-azidobutoxy)terephthalate (9): A mixture of di-
ethyl 2,5-dihydroxyterephthalate (7) (1.00 g, 3.9 mmol), 1-azido-4-
bromobutane[31] (8) (2.134 g, 12.0 mmol), potassium carbonate
(3.34 g, 24.2 mmol), potassium iodide (49 mg, 0.30 mmol), 18-
crown-6 (32 mg, 0.12 mmol) and dry acetone (30 mL) was heated
at 70 °C for 27 h. The reaction mixture was cooled and concen-
trated under reduced pressure. The mixture was then partitioned
between EtOAc and water. The organic layer was separated and
the aqueous layer was extracted with EtOAc. The combined or-
ganic layers were washed with brine (1ϫ), dried (Na2SO4), and
concentrated under reduced pressure. The resulting brown oil was
purified by flash chromatography (SiO2, 10% EtOAc/PE) to afford
1.407 g (80%) of 9 as a pale yellow oil. The product was crystallized
as colorless needles by cooling an ethereal solution that had been
layered with petroleum ether (PE) to –30 °C in a freezer; m.p. 37–
38 °C. C20H28N6O6 (448.48): calcd. C 53.56, H 6.29, N 18.74;
found C 53.63, H 6.03, N 18.60.
Scheme 2. Syntheses of the knot precursors 1.
trometry indicated that the products were isomeric, with
each giving rise to a molecular ion (M – 1) peak at
1560.9 Da. The molecular ion isotope pattern excluded the
Click Cycloaddition Product 10b:[20] Sodium ascorbate (77 mg,
0.39 mmol) was added to a mixture of 6b (904 mg, 1.51 mmol), 9
(334 mg, 0.74 mmol), copper sulfate pentahydrate (19.6 mg,
0.078 mmol), THF (12 mL), tert-butyl alcohol (5 mL), and water
(5 mL). The mixture was stirred vigorously at ambient temperature
for 23 h, after which time additional copper sulfate pentahydrate
(28 mg, 0.11 mmol) and sodium ascorbate (88 mg, 0.44 mmol) were
added and the mixture was stirred for an additional 3 h. The reac-
tion mixture was then diluted with water, Et2O, and EtOAc. The
organic layer was collected and the aqueous layer was extracted
with Et2O. The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. Purifica-
tion by flash chromatography (SiO2, compound loaded as a
CH2Cl2 solution: 30Ǟ100% EtOAc/PE) afforded 859 mg (70%) of
10b as a waxy white solid; m.p. 48.5–50.5 °C. C98H160N6O14
(1646.37): calcd. C 71.49, H 9.80, N 5.10; found C 71.63, H 9.70,
N 5.13.
1
possibility of a doubly charged dimer. IR and H NMR
spectroscopic data of the products were quite similar to
each other but some distinct differences were noted. Peaks
for E and Z internal alkenes were observed in both isomers.
One possible interpretation of these data is that one of the
products is the unknot (macrocycle) and the other is either
the trefoil or figure eight knot.[30] When 1a was subjected
to a similar RCM/ester hydrolysis sequence, five products
were isolated from a preparatory TLC plate. Electrospray
mass spectrometry showed that the products were isomeric
(M + 1 peak at 1306 Da) and the IR and 1H NMR spectro-
scopic data were quite similar to each other with all show-
ing peaks for both E and Z internal alkenes. Further struc-
ture elucidation experiments on the thread & cut products
from precursors 1a and 1b are in progress.
Terephthalic Acid Derivative 11b: A solution of KOH (214 mg,
3.82 mmol) in water (2 mL) was added to a solution of 10b
(134 mg, 0.081 mmol) in THF (6 mL) and ethanol (1 mL). The re-
sulting solution was heated at reflux for 2 h, cooled to ambient
temperature, and diluted with saturated aqueous ammonium chlo-
ride, Et2O, and EtOAc. The organic layer was collected, the aque-
Conclusions
A novel approach to molecular knots is described. The
bis-macrocyclic knot precursors 1a and 1b are efficiently
prepared via convergent six-step syntheses with overall ous layer was made acidic with 0.5  HCl and then extracted with
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E. E. Fenlon, B. R. Ito
SHORT COMMUNICATION
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concentrated under reduced pressure to give 132.9 mg (quantita-
tive) of 11b as a white solid that was a single spot via TLC (10%
MeOH/CH2Cl2); m.p. 66.5–68 °C.
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Knot Precursor o-1b
& m-1b: A solution of 11b (109 mg,
0.069 mmol) in CH2Cl2 (150 mL) was added to a mixture of
DMAP (58 mg, 0.47 mmol) and 2-methyl-6-nitrobenzoic anhy-
dride[29] (71 mg, 0.21 mmol), 4-Å molecular sieves, and CH2Cl2
(150 mL) over a period of 100 min. The resulting mixture was
stirred at ambient temperature for 45 h. The reaction mixture was
then concentrated under reduced pressure and the product was
purified by flash chromatography (SiO2, 5% MeOH/CH2Cl2) to
yield 86.3 mg (81%) of o-1b & m-1b as a white solid. On the basis
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Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and full characterization
data for all new compounds.
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Acknowledgments
We are grateful to Raymundo Alfaro-Aco for the syntheses of start-
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Strausser, and Ken Hess for their valuable assistance. This work
was supported by an award from Research Corporation, the Pepin-
sky Scholars Program, a Hackman Faculty Award, ACS Project
SEED, and the National Science Foundation (0412901) for the pur-
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Received: April 18, 2008
Published Online: May 13, 2008
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