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Molecular Machines Assemble Four Different Chemical Products
University of Manchester researchers have created a molecular machine that can assemble four different chemical products [acs.org]:
David A. Leigh of the University of Manchester and coworkers made molecular-machine-based chemical synthesis a reality four years ago when they developed a large molecule [acs.org] that picks up amino acids and assembles them into tripeptides (Science 2013, DOI: 10.1126/science.1229753 [doi.org]). Now, they've taken the concept to another level by creating a programmable molecular machine that creates four different products by adding thiol and alkene substituents asymmetrically to an α,β-unsaturated aldehyde substrate (Nature 2017, DOI: 10.1038/nature23677 [doi.org]). The machine makes each of the products with stereoselectivity similar to, but in some cases lower than, that of corresponding catalytic reactions in solution, Leigh says.
To generate the products, Leigh and coworkers attach an α,β-unsaturated aldehyde substrate to an "arm" in the molecular machine. An acyl hydrazone located in the center of the machine changes conformation in response to pH changes, causing the arm to rotate between two fixed orientations. Rotations position the substrate above one or another of two silyl prolinol activation sites in the machine that mediate reactions with opposite chirality—R for one site, S for the other. So arm position controls reaction chirality.
The substrate forms a reactive iminium intermediate with an activation site, and the intermediate then reacts with a thiol for the first addition. Then the substrate, with its added sulfide, forms a reactive enamine with an activation site, and the alkene adds to that. If the arm is rotated between the two activation sites mid-synthesis by adding acid, the steps have opposite chirality, and the diastereomer products have (R,S) or (S,R) configuration. If the arm is stationary between steps, both additions occur with the same chirality, and the product has (R,R) or (S,S) configuration.
