Final Report Summary - MOLFACTORY (Machinery for Molecular Factories) The widespread use of molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular systems—which by and large rely upon electronic and chemical effects to carry out their functions—and the machines of the macroscopic world, which utilize the synchronized movements of smaller parts to perform particular tasks. The aim of this project is to design, construct and investigate the operation of synthetic molecular machines capable of performing sophisticated tasks in chemical synthesis. Its successful demonstration would give mankind the beginnings of a potentially game-changing new approach for the synthesis of organic molecules.We have successfully developed strategies to design and construct three types of synthetic molecular machines – each one representing a significant development in the field of artificial molecular machines – namely, molecular machines that can operate via a robotic arm, molecular machines based on rotaxane architectures that can catalyse selected chemical reactions and machines that can operate continuously when powered by a chemical fuel.We have developed a wholly artificial small-molecule robotic arm that is capable of selectively transporting a molecular cargo in either direction between two spatially distinct, chemically similar, sites on a molecular platform (Nature Chemistry, 8, 138–143 (2016); and then applied this robotic arm design to construct and operate a molecular machine that moves a substrate between different activating sites to achieve different product outcomes from chemical synthesis (Nature, 549, 374–378 (2017). In our study of switchable catalysts, we exploited the mechanical bond of the rotaxane architecture to create a new class of enantioselective catalyst – and demonstrated its effectiveness in catalysing in two different organocatalytic reactions - one that proceeds through the formation of an iminium species and one that involves an enamine mode of activation (J. Am. Chem. Soc., 2016). This is the first time that an enantioselective catalyst that is chiral solely as a result of a mechanical bond has been demonstrated. We have also discovered another alternative switchable system based on a molecular knot (Science, 352, 1555 (2016)) - that can abstract a chloride or bromide ion from a halocarbon, to form a carbocation - that can then catalyse hydrolysis, Michael addition, and Diels–Alder reactions. We have developed a rotaxane-based molecular machine that synthesises β-peptides in a sequence-specific manner (J. Am. Chem. Soc., 2017, 139 (31), pp 10875–10879) and a small-molecule “walker” that uses enzyme catalysis to discriminate between the relative positions of its “feet” on a track and thereby move with net directionality (J. Am. Chem. Soc., 2017, 139 (34), pp 11998–12002). We have also developed a synthetic molecular motor system that consumes a single chemical fuel to power a molecular machine that achieves continuous rotary motion as long as the fuel is present, and does not require any further chemical input or external stimulus (Nature, 534, 235-240 (2016) and Science, 358, 340-343 (2017). . Significantly, these synthetic molecular motors use chemical energy to drive rotation, whereas before this, light energy had been the only source of energy that was used to drive a molecular system away from equilibrium. Nature uses molecular machines in every conceivable aspect of chemical synthesis. Biology has not evolved to do this over 2.5 billion years for no good reason and when chemists learn how to use directed molecular motion to build molecules—positioning substrates and machines and controlling the dynamics of reactive centres—the result will be a potentially game-changing new approach to functional molecule and materials synthesis. Applications of functional molecular machine systems could help reduce demand for materials, accelerate and improve drug discovery, reduce power requirements, facilitate recycling and reduce life-cycle costs. The 2016 Nobel Prize for Chemistry was awarded to Sauvage, Stoddart and Feringa ‘for the design and synthesis of molecular machines’, in recognition of the potential of the field of ‘molecular robotics’ to become one of the next major scientific areas.
