Molecular Machines with a Robotic Arm that can Control the Stereochemistry of Catalyzed Reactions

• Applicant: Dr. Marcel Dommaschk
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321165850

The project is about the synthesis of molecular machines that can control the stereochemistry of catalyzed reactions. The machines have a robotic arm (rotor) to which the starting material is attached and a stator equipped with two catalytic moieties of opposite handedness. The position of the rotor is supposed to control which active site is catalyzing the reaction and thus is crucial for the stereochemistry of the product. The concept should in principle be applicable to any kind of chiral catalysis.The first proposed machine bears two proline catalysts to activate aldehydes for two sequential reactions (domino reaction). The first one is an iminium activation (functionalization of the beta position) followed by an enamin activation (functionalization of the alpha position). Thus, there are four possible diastereomeric products. The activation site for each reaction can be controlled by the position of the robotic arm. Hence, the proposed machine should be able to synthesize each diastereomer selectively.The switching unit is the centrepiece of the machine. To favour one of the two catalytic sites for the aldehyde activation the robotic arm (rotor) should preferable rotate 180°. During this process the stator (bearing the catalytic sites) must be stationary. Such a movement on a molecular level can be achieved by rotation of a double bond. The E/Z isomerization of hydrazones has proved to be successful for this purpose. The isomerization can easily be controlled by the pH. A molecular machine can only provide a high enantiomeric excess if the E/Z switching is quantitative. The first task of this project will be the development of a suitable hydrazone switch. The most promising hydrazone derivative will be utilized for the molecular machine.The machine should be obtained by a convergent synthesis. Rotor and stator are synthesized independently before connected to each other. The last step is the attachment of the starting material (alpha, beta unsaturated aldehyde) to the rotor part. A disulfide bond enables releasing the product after the catalytic reactions. The aldehyde is supposed to react initially with a nucleophile (iminium activation) and subsequently with an electrophile (enamine activation). Afterwards the product can be analyzed by chiral chromatography. Ideally only one of the four possible diastereomers is obtained. If this is the case the machine would be able to synthesize every desired diastereomer by switching the hydrazone before the iminium activation and/or the enamin activation.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor David A. Leigh, Ph.D.