Stereodivergent synthesis with a programmable molecular machine

A molecular machine that can be programmed to position a substrate at one of two directing sites on a molecule, which control the stereochemistry of addition to the substrate, demonstrates complexity, precision and function previously only observed in nature. Unnatural diastereoisomers It has been debated whether synthetic molecular machines could ever rival the complexity, precision and function of evolved biological machinery, with questions arising over whether atom-by-atom construction of molecules is possible, practicable or scalable. Key to the function of a hypothetical 'molecular assembler' is the ability of the machinery to position reactants. David Leigh and colleagues now use a molecular machine that can 'pick up' a substrate and position it at one of the two directing sites on the machine that control the stereochemistry of addition to the substrate. For two sequential chemical reactions, and depending on how the machine is programmed to move the substrate in between reactions, the molecular robot could make any one of four possible diastereoisomers, including one that cannot be made through conventional organocatalytic reactions. It has been convincingly argued 1 , 2 , 3 that molecular machines that manipulate individual atoms, or highly reactive clusters of atoms, with Ångström precision are unlikely to be realized. However, biological molecular machines routinely position rather less reactive substrates in order to direct chemical reaction sequences, from sequence-specific synthesis by the ribosome 4 to polyketide synthases 5 , 6 , 7 , where tethered molecules are passed from active site to active site in multi-enzyme complexes. Artificial molecular machines 8 , 9 , 10 , 11 , 12 have been developed for tasks that include sequence-specific oligomer synthesis 13 , 14 , 15 and the switching of product chirality 16 , 17 , 18 , 19 , a photo-responsive host molecule has been described that is able to mechanically twist a bound molecular guest 20 , and molecular fragments have been selectively transported in either direction between sites on a molecular platform through a ratchet mechanism 21 . Here we detail an artificial molecular machine that moves a substrate between different activating sites to achieve different product outcomes from chemical synthesis. This molecular robot can be programmed to stereoselectively produce, in a sequential one-pot operation, an excess of any one of four possible diastereoisomers from the addition of a thiol and