A Short Covalent Synthesis of an All-Carbon-Ring [2]Rotaxane

Article abstract of DOI:10.1021/acs.orglett.7b00877

While the current supramolecular syntheses of [2]rotaxanes are generally efficient, the final product always retains the functional groups required for non-covalent preorganization. A short and high-yielding covalent-template-assisted approach is reported

Full text of DOI:10.1021/acs.orglett.7b00877

Letter
pubs.acs.org/OrgLett
A Short Covalent Synthesis of an All-Carbon-Ring [2]Rotaxane
Luuk Steemers,† Martin J. Wanner,† Andreas W. Ehlers,†,‡ Henk Hiemstra,†
and Jan H. van Maarseveen*,†
†Van’t Hoff Institute for Molecular Chemistry, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
‡Department of Chemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa
S
* Supporting Information
ABSTRACT: While the current supramolecular syntheses of [2]rotaxanes are generally efficient, the final product always retains
the functional groups required for non-covalent preorganization. A short and high-yielding covalent-template-assisted approach is
reported for the synthesis of a [2]rotaxane. A terephthalic acid template core preorganizes the covalently connected ring
precursor fragments to induce a clipping-type cyclization over the thread moiety. Cleavage of the temporary ester bonds that
connect the ring and thread fragments liberates the [2]rotaxane.
oth the synthesis of rotaxanes and their applications in
Bespecially materials research have become increasingly
important over the last 25 years, as indicated by the award of the
2016 Nobel Prize in Chemistry. In contrast to the vast number of
publications on rotaxanes, the available synthetic strategies are
somewhat limited. For the preparation of threaded molecules, in
general three main strategies exist.1 The first is clipping-type
cyclization of the ring precursor over the thread fragment. The
second is capping of the ends of a thread that is non-covalently
bound within a macrocycle. Finally, approaches have been
reported in which two thread fragment precursors are connected
by a reaction that is promoted by an active metal that is bound
within the macrocycle. In essence, all of these synthetic methods
rely on non-covalent interactions such as H-bonding,2 crown
ether−ammonium,3 π−π,4 and metal ion interactions.5 In all of
these methods, the motif used for preorganization is retained in
the final product. Usually this is of no consequence, and it can be
even desirable for the formation of functional spots (stations) on
the thread. Nevertheless, the structural diversity of rotaxanes is
somewhat restricted because of the specific functional groups
that are required as supramolecular handles for these synthetic
strategies. To make such “impossible” rotaxanes, alternative
strategies are required, such as late-stage modifications or a
strategy obviating non-covalent recognition elements.6 Interest-
ingly, the first rotaxane and catenane syntheses were reported
covalent interactions are present between ring and thread
fragments in the final mechanically interlocked molecules. In the
same period a statistical approach to a [2]rotaxane was reported
starting from an all-carbon-ring fragment.8 Although low-
yielding, this strategy led to an “impossible” rotaxane lacking
interactions between the ring and thread fragments. Since those
early pioneers, covalent approaches have remained a niche, and
over the last two decades only a few successful covalent
approaches toward “impossible” rotaxanes and catenanes have
been reported.9 Most recently, the Hoger group reported the use
̈
of a terephthalic acid template as a temporary covalent template
for the synthesis of a [2]rotaxane.9g On the basis of an earlier
unsuccessful approach toward [2]rotaxanes by Morin, a huge 50-
membered-ring pre-rotaxane was constructed after clipping by
two consecutive Glaser couplings of two fragments that were
both covalently attached as phenol esters over the templating
terephthalic acid core.10,11 Next, the bulky stopper elements were
installed at the terephthalate core 2- and 5-positions, followed by
ester cleavage via aminolysis using n-propylamine to liberate the
[2]rotaxane.
Inspired by these reports, we set out to synthesize a
[2]rotaxane, 1, using a terephthalic acid template toward a
relatively small ring system in the range of most commonly
described rotaxanes (Scheme 1). For the macrocyclization
reaction, the proven Ru-catalyzed ring-closing metathesis
back in the 1960s by Schill and Luttringhaus and relied on
̈
covalent-template-directed macrocyclizations followed by lib-
eration of the free [2]rotaxanes or catenanes after cleavage of
temporary bonds as the last step.7 Consequently, no non-
Received: March 24, 2017
© XXXX American Chemical Society
A
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Scheme 1. Outline of the Synthetic Strategy to [2]Rotaxanes 1 via a Terephthalic Acid Template
Scheme 3. Synthesis of Terephthalic Acid Template 17
Figure 1. Design of the covalent [2]rotaxane precursor 2.
Scheme 4. Synthesis of Azide-Functionalized Stopper 22
Scheme 2. Synthesis of Macrocycle Precursor 10
thread fragment bearing the stopper elements, giving bisester 2
(see Figure 1). Semiempirical models at the PM6 level showed
that after the first RCM reaction both phenol rings are locked in a
perpendicular arrangement with respect to the terephthalic core
(Scheme 1, route A, compound 3). As a result, in the second
RCM reaction the two remaining alkenyl chains are well-
positioned to cyclize in a clipping fashion over the ring fragment
to give pre-rotaxane 4. Cleavage of the terephthalate esters by
transesterification liberates the mechanically locked [2]rotaxane
1. Besides the usual intermolecular oligomerization reaction, two
(RCM) reaction appeared most suitable. Besides its robustness,
RCM obviates the need for protecting groups.12
In our modification of the approaches of Hoger and Morin,
̈
both using short tethers, the 2,6-di-ω-alkenyl ring fragment
phenols were directly esterified to form the terephthalic acid
B
DOI: 10.1021/acs.orglett.7b00877
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Scheme 5. Assembly of [2]Rotaxane 1
potential side reactions (Scheme 1, route B) may take place
during macrocyclizations despite the terephthalate-moiety-
driven preorganization. First, as a competitive ring closure, the
alkenyl chains attached at the same phenol may cyclize to give
two isolated cycloalkenes as in 5. Second, the desired macrocycle
may cyclize in a noninterlocked manner to give 6. In the
unsuccessful approach by the Morin group, this latter undesired
pathway had indeed occurred because of a too-flexible linker
between the phenol and the ester.10
In the current synthetic route, the phenols are directly
esterified to the terephthalic acid (see Figure 1) to introduce
more conformational constraints, hampering these potential side
reactions. DFT calculations at the PM6//wB97XD/6-31G(d)
level of theory showed conformers 5 and 6 to actually be higher
in energy than 4 by 18.1 and 31.4 kcal/mol, respectively (see the
Supporting Information). This suggests that the dynamics of
succeeding ring-opening/ring-closing metathesis steps may favor
the thermodynamically most stable product 4.
terminal alkynes allowed installation of the bulky stopper groups
via Cu(I)-catalyzed azide−alkyne cycloaddition (CuAAC).
It is worth mentioning that the very bright blue fluorescence of
the terephthalate moiety under UV light at both 254 and 355 nm
allows for easy identification of products on TLC. Product 15
was smoothly saponified with KOH, and the resulting carboxylic
acid groups of 16 were activated as pentafluorophenol esters
using HBTU as the coupling reagent, giving 17 in 79% yield. As
the stopper unit, the tris(4-tert-butyl)trityl group was chosen,
attached to a flexible azidoethane linker.15 The stopper synthesis
(see Scheme 4) started by lithiation of 4-tert-butylbromobenzene
(18) followed by quenching with dimethyl carbonate to give
trityl alcohol 19 in 84% yield.15a Subsequent reaction with
malonic acid at elevated temperature yielded propionic acid
derivative 20, which was subsequently reduced by borane−
dimethyl sulfide complex in 76% overall yield.15b Transformation
of the resulting alcohol 21 into the desired azide 22 via the
Mitsunobu reaction proceeded in 79% yield.
For the synthesis of the 2,6-difunctionalized phenol (see
Scheme 2), 4-tert-butylphenol (7) was chosen as the starting
material to block the 4-position during iodination and ensure the
solubility of intermediates. Iodination of 7 followed by MOM
protection gave 8 in 80% yield over the two steps.13 Subsequent
Sonogashira reaction with 5-hexyn-1-ol and catalytic hydro-
genation yielded 9 in 92% overall yield. Parikh−Doering
oxidation of the alcohols followed by Wittig reaction completed
the synthesis of the 6-heptenyl arms. A final MOM removal with
concentrated aqueous HCl in THF gave the desired phenol-
based macrocycle precursor 10 in quantitative yield.
With all of the building blocks in hand, the convergent
assembly of the rotaxane skeleton commenced with coupling of
the activated terephthalic template 17 via transesterification with
the sterically congested phenol 10 using Cs2CO3 as the base (see
Scheme 5). Gratifyingly, clean and full conversion was observed
to give terephthalate 23 in 91% isolated yield. To avoid
hydrolysis of the activated pentafluorophenyl esters, 4 Å
molecular sieves were added. Installation of the stopper groups
had to be done at this stage because subsequent Ru-catalyzed
olefin metathesis would lead to competing ene−yne metathesis
reactions.16 CuAAC coupling between 23 and 22 (2 equiv) using
CuI, DIPEA, and 2,6-lutidine as the catalytic system in
acetonitrile gave the rotaxane precursor 2 cleanly in 87% yield.
The sequential clipping RCM reactions of the alkenyl chains over
the thread fragment were performed using 20 mol % Grubbs
The synthesis of the terephthalic acid template (see Scheme 3)
started from 11, NCS-mediated oxidation of which gave 12.
Subsequent alkylation with 14 (obtained via mesylation of 4-
pentyn-1-ol (13)) provided compound 15 in 78% yield.14 The
C
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Notes
second-generation catalyst at high dilution (1 mM) to prevent
competing intermolecular reactions and solely gave the
anticipated pre-rotaxane 4 in 80% yield as an E/Z mixture of
isomers. Catalytic hydrogenation to remove this mixture was
performed at 60 °C to ensure full conversion and gave pre-
rotaxane 4-H4 in almost quantitative yield.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank The Netherlands Organization for Scientific
Research (NWO-CW, ECHO Grant 711.012.009 to J.H.v.M). E.
Zuidinga and J. M. Ernsting (University of Amsterdam) are
acknowledged for mass spectrometry and NMR assistance.
Despite the absence of the olefinic E/Z mixture, the 1H NMR
spectrum remained complex with broad signals (see the
Supporting Information), indicating a nonsymmetric arrange-
ment of the ring fragment. A first sign that indeed the rotaxane
architecture had been obtained was the fact that the final cleavage
steps to liberate the mechanically interlocked [2]rotaxane
skeleton required harsh conditions to overcome the steric
hindrance around the endocyclic ester bonds. Unexpectedly,
reaction with excess methylamine at 50 °C, used in a similar case
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̈
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00877.
Full experimental and characterization data for all
compounds and the coordinates and structures from the
theoretical calculations (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.h.vanmaarseveen@uva.nl.
ORCID
Jan H. van Maarseveen: 0000-0002-1483-436X
D
DOI: 10.1021/acs.orglett.7b00877
Org. Lett. XXXX, XXX, XXX−XXX