Within living organisms in the natural world, highly complex systems have evolved over billions of years to carry out the specific synthetic functions required to support and propagate life. Nature's use of biological machines for the synthesis of functional molecules has inspired synthetic chemists from a broad range of specialisms to design artificial molecular machines and systems capable of facilitating non-trivial synthetic tasks. A core strategy employed in attempting to emulate biological machines for synthesis has been to mimic Nature's ability to compartmentalise discrete aspects of a synthetic process. Rotaxanes are favourable architectures around which to design molecular machines as their mechanically-interlocked nature provides the chemist with a unique means by which to achieve compartmentalisation and to control the effective molarity of non-covalently linked components. The research presented in this thesis investigates the design, synthesis and operation of novel, rotaxane-based molecular machines for the non-trivial assembly of individual amino acid building blocks into information-rich oligopeptides. The artificial devices described herein each endeavour to emulate (in a primitive manner) one of Nature's most remarkable machines for synthesis: the ribosome. Information is programmed into these 'synthetic ribosomes' through their careful design and modular assembly; upon operation of the artificial molecular machine, this transcribed information is translated into a pre-defined oligopeptide product. The research presented in this thesis is laid out as follows:Chapter 1 reviews the current state of the art in biomimetic molecular machines and systems capable of promoting non-trivial synthetic tasks;Chapter 2 describes a molecular machine capable of non-proteinogenic oligopeptide synthesis via the sequence-specific assembly of beta-homo amino acid building blocks;Chapter 3 presents a device which operates upon a polymer to assemble individual leucine units into a homo-oligopeptide. This product forms a secondary alpha-helical structure capable of asymmetric organocatalysis in the Juliá-Colonna epoxidation of chalcone derivatives;Chapter 4 details a novel mode of amide-bond-forming catalysis for rotaxane-based molecular machines with a view to assembling an advanced peptidic precursor to Penicillin G.Chapters 2 and 3 are presented as manuscripts which have been compiled for peer-review publication and which represent the collaborative efforts of the Author and the researchers indicated at the beginning of each chapter. The Author's contributions are also outlined at the beginning of each chapter. These manuscripts have been modified only to ensure consistency with the other chapters contained in this thesis.

This work describes the design, synthesis and operation of a (R,R)-(+)-hydrobenzoin-diacetic acid molecular walker attached to polyether tracks containing 2, 3 or 4 secondary alcohol footholds. A macrocycle-the walker attached to a 2-foothold track by two ester linkages-was regioselectively hydrolysed by lipase AS. The resultant seco¬-acid was recyclised using Yamaguchi chemistry, demonstrating a bipedal walker stepping off, and on to, a track. These conditions were extended to tracks containing 3 and 4 alcohol footholds and the design of a 3-foothold track that incorporated a pentaethylene glycol chain. Using an information type Brownian ratchet mechanism, ~90% of walkers stepped away from the starting position, and ~68% of walkers took 2 steps to a foothold 16 atoms away. Importantly only smaller or equal to4% of walkers were found to completely detach from the track per operation cycle.

The concept of tiny machines capable of selectively transporting particles between two compartments by Brownian motion dates back to the 19th century when James Clerk Maxwell pondered the significance of a hypothetical ‘sorting demon’ being able to perform such a task adiabatically. This thesis report the design, synthesis and operation of a compartmentalized molecular machine in which the distribution of a Brownian particle, the macrocycle in a rotaxane, is controlled by using the lightinduced transmission of information to lower a kinetic barrier according to the location of the particle. For an ensemble of such machines the particle distribution is driven further and further away from equilibrium, providing a non-adiabatic realization of Maxwell’s pressure demon in molecular form. The nanomachine does not break the Second Law of Thermodynamics because the energy cost of the information transfer is met by externally supplied photons. As the molecular structure can be understood in chemical terms, it is possible in this experimental system to pin-point precisely how information is traded for energy. Intriguingly, the chemical mechanism can also be understood in terms of game theory. This is the first example of a synthetic molecular machine designed to operate via an information ratchet mechanism, where knowledge of the object’s position is used to control its transport away from equilibrium.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The description of this thesis is divided into three chapters following the chronological events of my research development. In chapter one, a series of new 1,4-anthracenediones were synthesized via functionalizations of the methyl side chain of 6-methyl-1,4-anthracenedione. The new 1,4-anthracenediones were found to exhibit potent cytotoxic activities against human L1210 leukemic and HL-60 cell lines. A key intermediate, 6-bromomethyl-1,4- anthracenedione (1.44), was first synthesized through a sequence of reactions including a double Friedel-Crafts reaction, reductive quinone formation, and selective benzylic bromination. The bromide (1.44) was further converted to other 1,4-anthracenediones via hydrolysis, subsequent oxidation, and reductive amination or nucleophilic substitution. Chapter two deals with a continuous research project aiming at macropolycyclic cyclodecitycene or [10]beltene derivative using Diels-Alder reaction as the key strategy for cyclization. A tetraene, (4aR,5R,7S,7aS,11aR,12R,14S,14aR)-5,7,12,14-tetrahydroxy- 2,3,9,10-tetramethylene-1,4,4a,5,6,7,7a,8,11,11a,12,13,14,14a-tetradecahydro-6,13-obenzenopentacene (2.51), was synthesized by following previous work from this laboratory. Unfortunately, the Diels-Alder reaction of tetraene 2.51 with triptycene bisquinone showed predominantly polymerization over intramolecular cyclization. The use of double activated quinone such as 1,4,5,8-naphthodiquinone (2.64) and 1,2,4,5- tetraethoxycarbonyl-1,4-benzoquinone (2.70) as dienophiles gave monoadducts 2.67 and 2.71 respectively. However, they both failed to cyclize under high dilution conditions at elevated temperature, which may be rationalized by chair conformations adopted in six membered rings causing unfavorable twist for intramolecular cylization. Further study showed tetraene 2.51 underwent an unexpected furan ring forming reaction. In chapter three, an unprecedented substituted cyclododeciptycene, 2,4,6,8,10,12,14,16,18,20,22,24-dodecahydro-9,11,21,23-tetramethoxy-(2,14:4,16:6,18:8, 20:10,22:12,24)-hexa(o-benzeno)-[12]cyclacene-1,3,5,7,13,14,17,19-octaone (3.138), was successfully synthesized based on a successful intramolecular Diels-Alder reaction, which was developed from the above [10]beltene project and previously reported literature work. A series of all cis-iptycenequinones were synthesized as bisdienophile building blocks from a sequence of Diels-Alder reactions, separation of individual Diels- Alder adducts, enolization, and oxidative demethoxylation. It was found that each Diels- Alder adduct isomer shows distinguish [superscript]1HNMR signals inherent to its structure. The characteristic [superscript]1HNMR signals allow the identification of the structures of iptycenequinones derived from the above reactions. A bisdimethoxyanthracene, 6,8,15,17-tetramethoxy-7,16-dihydro-7,16-(o-benzeno)heptacene (3.56), was synthesized as bisdiene building block, which reacted with cis,cis-heptiptycene tetraquinone (3.23). The cycloadduct was transformed to cyclododeciptycene 3.138, whose structure was firmly established by a single-crystal X-ray analysis.

This thesis explores the use of anions in the design and construction of interlocked architectures for applications in anion recognition and sensing, and to function as molecular machines upon a given stimulus. Chapter One introduces the field of anionic supramolecular chemistry focusing on host-guest chemistry and directed self-assembly. A review of the recognition and sensing of anionic guest species is given before strategies for the construction of interlocked architectures are discussed, and the potential functions of these structures considered. Chapter Two details the development of a novel anion-templation route for the synthesis of macrocycles and rotaxanes. The versatility of this route in constructing new [2]rotaxanes is explored by varying several features of the macrocyclic component, with emphasis on creating the most powerful anion complexant. Proton NMR spectroscopy is used to probe the anion binding properties of the rotaxanes, and X-ray crystallography and MD simulations are used to rationalize anion binding trends. The possibility of synthesizing catenanes for anion recognition via this new synthetic route is also investigated. Chapter Three investigates the appendage of transition metal complexes to rotaxanes to create interlocked host architectures capable of sensing anions via luminescence spectroscopy. The incorporation of rhenium(I) and ruthenium(II) polypyridyl complexes into the macrocyclic and axle component of [2]rotaxanes are described, before the anion binding studies of these structures using ¹H NMR and luminescence spectroscopy are reported. Chapter Four describes the strategic synthesis of [2]rotaxanes designed to undergo molecular motion upon a given stimulus. Initially, the possibility of exploiting anions to stimulate the macrocyclic component of the [2]rotaxanes to translocate to a second station on the axle is investigated. The use of pyridine N-oxide as an integrated template for rotaxane formation is reported before the ability of these rotaxanes to undergo anion and pH driven molecular motion is explored. This chapter concludes with the construction of a calix[4]diquinone N-oxide containing [2]rotaxane capable of undergoing sodium- and barium-induced molecular pirouetting. Chapter Five provides synthetic procedures and characterisation details for compounds listed in this thesis. Chapter Six reports supplementary experimental information including titration protocols, X-ray crystal structures and MD simulations.

Cette thèse est dédiée à la conception de synthons entrelacés pour la préparation efficace de machines moléculaires pH-sensible de type rotaxane et de rotaxanes dénués de site de reconnaissance. Bien que la stratégie dirigée par l’effet « template » ait été employée très fréquemment et avec succès à ce jour, elle ne mène dans la plupart des cas qu’à des composés entrelacés qui contiennent les sites d’interactions nécessaires à la reconnaissance préalable des éléments moléculaires à assembler. Pour remédier à cette limitation, une nouvelle voie d’accès directe utilisant des synthons entrelacées pour la préparation de machines moléculaires de type rotaxanes et de rotaxanes dénués de site d’interaction fort a été étudié. Dans un premier temps, des « briques moléculaires » [2]rotaxanes isolables, bien qu’activées, ont été obtenus par une stratégie de glissement. Dans le but de les convertir aisément en machines moléculaires, les paramètres cinétiques et thermodynamiques relatifs au processus d’entrelacement ont été déterminés et ont permis de juger de l’importance de la nature et de l’orientation des pseudo-bouchons sur la cinétique d’entrelacement, ainsi que du rôle primordial du degré de liberté conformationnel de l’axe moléculaire sur la vitesse de formation des rotaxanes. Par la suite, les synthons entrelacées activés sous forme d’ester actif (ester de NHS isolable) sont utilisées dans la préparation de différentes machines moléculaires possédant une station moléculaire principale ammonium et une station moléculaire secondaire triazolium ou amide (secondaire ou tertiaire). D’autres synthons entrelacés qui différent par l’orientation du motif NHS sont utilisé comme transporteurs d’éther couronne pour permettre la préparation de rotaxanes dénués de site d’interaction fort. Enfin, dans la continuité des travaux réalisés au laboratoire sur le contrôle de la conformation chaise d’un mannosyl par une machinerie moléculaire, de nouvelles navettes pH-sensible de type glyco[2]rotaxanes contenant toutes une station moléculaire principale anilinium, et qui différent des machines précédentes par la deuxième station pyridinium, ont été obtenus et étudiés. / This thesis is dedicated to the synthesis of interlocked synthons for the efficient preparation of pH-sensitive rotaxane molecular machines and rotaxanes devoid of recognition site. Although the strategy directed by the "template" effect has been used very frequently and successfully so far, in most cases it only leads to interlocked compounds that contain the interaction sites necessary for prior recognition molecular elements to assemble. To overcome this limitation, a new direct access using interlocked synthons for the preparation of molecular machines of the rotaxane and rotaxane type devoid of strong interaction sites has been studied. Firstly, isolable [2]rotaxane "building block", although activated, were obtained by a slipping strategy. In order to easily convert them into molecular machines, the kinetic and thermodynamic parameters relating to the slipping process were determined and made it possible to judge the importance of the nature and orientation of the pseudo-stopper on the kinetics of slipping, as well as the primordial role of the degree of conformational freedom of the molecular axis on the speed of formation of rotaxanes. Subsequently, the activated ester (NHS isolatable ester) interlocked synthon are used in the preparation of different molecular machines having a main ammonium molecular station and a secondary molecular triazolium or amide station (secondary or tertiary). Other interlocked synthons that differ in the orientation of the NHS motif are used as crown ether transporters to enable the preparation of rotaxanes devoid strong interaction sites. Finally, in the continuity of the work carried out in the laboratory on the control of the chair conformation of a mannosyl by a molecular machinery, new pH-sensitive shuttles of glyco[2]rotaxane containing a main molecular station anilinium, and which different previous machines by the second station pyridinium, were obtained and studied.

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Un défi dans le domaine des nanotechnologies consiste à coupler des mouvements moléculaires individuels bien définis pour produire une réponse macroscopique.Dans nos travaux, nous avons pu démontrer, pour la première fois et de manière originale, la contraction et l’extension micrométrique de polymères supramoléculaires téléscopiques. En particulier, des rotaxanes mécaniquement entrelacés et possédant deux stations aux affinités modulables ont été fonctionnalisés par des unités de coordination, permettant ainsi leur polymérisation en présence d’ions métalliques. L’utilisation de techniques de diffusion du rayonnement en solution a démontré la présence de chaines polymères supramoléculaires uniques présentant un très haut poids moléculaire. La variation du pH a ensuite permis d’obtenir les nano‐ contractions et extensions coopératives des rotaxanes individuels conduisant aux mouvements amplifiés de type muscle des chaines supramoléculaires avec des changements de leur longueur de contour de l’ordre de plusieurs micromètres. Un autre exemple consistant en un monomère rotaxane fonctionalisé à ces extrémités par des unités pyridines bis‐imides, pouvant former des liaisons hydrogènes avec un connecteur approprié, a permis de combiner plusieurs niveaux d’organisation hiérarchique. Des études par microscopie électronique à transmission ont mis en évidence la formation de « fagots » de fibres présentant un aspect de muscle. Ce travail représente le premier exemple démontrant la synchronisation de milliers de machines moléculaires à des échelles différentes et est considéré, en lui‐même, comme une avancée majeure en chimie supramoléculaire à l’interface avec les nanotechnologies. / One of the targeted challenges in nanotechnologies consists in coupling together defined individual molecular motions for the production of macroscopic response. Herein we have developed for the first time innovative micrometric contraction and extension of telescopic supramolecular polymers. In particular, mechanically interlocked and switchable double threaded rotaxanes have been tailored with coordination functions and subsequently polymerized in the presence of metal ions. Characterizations by scattering techniques in solution reveal the formation of single-strand supramolecular polymer chains with very high molecular weight (up to 8 × 106 g.mol-1). The subsequent pH modulation triggers cooperative nano-contractions / extensions of the individual rotaxanes resulting in an amplified motion of the muscle-like supramolecular chains with changes of their contour lengths by several micrometers.In another example, consisting in a rotaxane monomer ended by pyridine bis-imide units which can form donor-acceptor-donor type H-bonding with an appropriate connector, we were able to combine several level of hierarchical organization. The acid / base titration process of the rotaxane and the corresponding polymer with the connector was studied by 1H NMR and neutron scattering. TEM studies showed the formation of bundles of fibers with a muscle-like aspect.This work represents the first example showing this synchronization of thousands of molecular machines to cross several length scales and as such, it is considered as a major step in supramolecular chemistry at its interface with nanotechnologies.