.
Angewandte
Communications
DOI: 10.1002/anie.201200822
Molecular Walkers
A Small Molecule that Walks Non-Directionally Along a Track
Without External Intervention**
Araceli G. CampaÇa, Armando Carlone, Kai Chen, David T. F. Dryden, David A. Leigh,*
Urszula Lewandowska, and Kathleen M. Mullen
Kinesin, dynein, and some myosin motor proteins transport
cargoes within the cell by “walking” along polymeric fila-
ments, that is carrying out successive, repetitive, mostly
directional changes of their point of contact with the
molecular track without completely detaching from it.[1]
These extraordinary biomolecules are inspiring scientists to
mimic aspects of their dynamics to create artificial molecular
transport systems.[2,3] Recently, the first small molecules that
are able to walk down short molecular tracks were de-
scribed.[2] However, external intervention (the addition of
chemical reagents and/or irradiation with light) are required
to mediate each step taken by the walker units in the non-
DNA systems reported to date. Although migrations of
submolecular fragments occur in many different types of
Scheme 1. a) The migration of an ETAC[6] reagent between nucleophilic
sites of a protein by Michael/retro-Michael reactions towards the most
chemical reaction,[4] few systems appear to offer the potential
for multiple successive and cumulative transport necessary for
developing small-molecule walkers.[5] An interesting excep-
tion are the so-called equilibrium transfer alkylating cross-
linking (ETAC) reagents introduced in the 1970s by Lawton
and co-workers for the dynamic cross-linking of biomole-
cules.[6,7] These reagents reversibly form covalent bonds
between pairs of accessible nucleophilic sites on proteins
through a series of inter- and intramolecular Michael and
retro-Michael reactions until the most thermodynamically
stable crosslink is located (Scheme 1a).[6a] We wondered
whether it would be possible to apply a similar concept,
focusing instead on chemistry where the cross-linked products
are less stable than those attached by a single covalent bond,
to make synthetic small molecules that migrate with a high
degree of processivity[8] along a linear molecular track.
thermodynamically stable cross-linked product. b) Processive (intra-
molecular) migration of a-methylene-4-nitrostyrene along a polyamine
track. Michael addition of a track amine group to the olefin of the
“two-legged walker” results in a bridged intermediate (both “feet”
attached to the track, shown in square brackets) that can subsequently
undergo a retro-Michael reaction to either side, unmasking the double
bond and leaving the walker attached to the track through a single
covalent bond.
Herein we describe the attachment of a-methylene-4-
nitrostyrene to oligoethylenimine tracks and the dynamics of
its subsequent migration from amine group to amine group
without fully detaching by a sequence of intramolecular
Michael and retro-Michael reactions. In this way the a-
methylene-4-nitrostyrene units move towards the most ther-
modynamically favored distribution of walkers on oligoamine
tracks (Scheme 1b).[9]
A model walker-track conjugate, 1, was synthesized in
which a-methylene-4-nitrostyrene was attached to an outer
amine group of a triamine track and then allowed to exchange
between the secondary amine footholds (Scheme 2a; see the
Supporting Information for experimental procedures and
characterization data). The reaction was followed by
1H NMR spectroscopy through the different chemical shift
of vinyl protons (Hc/c’ and Hd/d’) of isomers 1 and 2 (Figure 1).
The kinetics of the amine-to-amine migration of the a-
methylene-4-nitrostyrene unit (“walking”) is highly solvent-
dependent. Starting from pristine 1 (5 mm), no formation of 2
was observed in CDCl3 or CD2Cl2 over 15 h at room
temperature and the reaction only proceeded slowly in
CD3OD (< 10% conversion over 15 h) or CD3CN (< 25%
conversion over 15 h). However, the interconversion of 1 with
2 reached a close-to-1:1 steady-state ratio of 1:2 over 15 h in
[D7]DMF or 4.5 h in [D6]DMSO (298 K, 5 mm). Increasing
[*] Dr. A. G. CampaÇa, Dr. A. Carlone, Dr. K. Chen, Dr. D. T. F. Dryden,
Prof. D. A. Leigh, U. Lewandowska, Dr. K. M. Mullen[+]
School of Chemistry, University of Edinburgh
The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ (UK)
Prof. D. A. Leigh
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (UK)
E-mail: david.leigh@manchester.ac.uk
[+] Current address: Science and Engineering Faculty, Queensland
University of Technology
GPO Box 2434, Brisbane, 4001 (Australia)
[**] We thank Prof. Richard Lawton (University of Michigan) for many
useful discussions and the EPSRC National Mass Spectrometry
Service Centre (Swansea (UK)) for high resolution mass spec-
trometry. This research was funded by the ERC. A.G.C. thanks the
Fundaciꢀn Ramꢀn Areces (Spain) for a postdoctoral fellowship.
Supporting information for this article is available on the WWW
5480
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 5480 –5483