The conversion of energy into controlled motion plays an important role in both man-made devices and biological systems. The principles of operation of conventional motors are well established, but the molecular processes used by 'biological motors' such as muscle fibres, flagella and cilia to convert chemical energy into co-ordinated movement remain poorly understood. Although 'brownian ratchets' are known to permit thermally activated motion in one direction only, the concept of channelling random thermal energy into controlled motion has not yet been extended to the molecular level. Here we describe a molecule that uses chemical energy to activate and bias a thermally induced isomerization reaction, and thereby achieve unidirectional intramolecular rotary motion. The motion consists of a 120 degrees rotation around a single bond connecting a three-bladed subunit to the bulky remainder of the molecule, and unidirectional motion is achieved by reversibly introducing a tether between the two units to energetically favour one of the two possible rotation directions. Although our system does not achieve continuous and fast rotation, the design principles that we have used may prove relevant for a better understanding of biological and synthetic molecular motors producing unidirectional rotary motion.

A proof of principle of the first rationally designed, chemically powered, molecular-scale motor is described. The thermodynamic considerations leading to the choice of 6a and 7a as the initial prototypes are provided, and the synthesis of 6a and 7a and the separation of them from their atropisomers are detailed. The phosgene-powered unidirectional rotation of 6a to its rotamer 6b is demonstrated. It is further established that shortening the length of the tether (→7a) changes the rate-limiting step and accelerates the speed of rotation.

An economic, scalable process for the production of glucosylceramide synthase (GCS) inhibitor 7 has been developed. Herein we report a three-step synthesis to aldehyde 4 with high yield and purity that employs the selective cleavage of an endocyclic CÀO bond of a THP ether using borane/THF as the key step. This particular methodology has not been used previously from a development standpoint and offers an attractive way towards introducing pentanol side chains. Aldehyde 4 is then coupled with deoxynojirimycin via flow hydrogenation using an H-Cube to safely produce the free base of 7, which is isolated as an MSA salt in 50% overall yield. Herein we discuss the evolution of this process from its original form and the thermodynamics of its associated chemistry.

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