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Iterative assembly line synthesis of polypropionates with full stereocontrol

The image shows a hypothetical molecular assembly line where reagents are effectively added to a growing carbon chain with extraordinary high fidelity and precision. By controlling the precise orientation of the building blocks added to the carbon chain, and which building blocks are used (creating hydroxyl group or methyl groups along the carbon chain), polyketide-like molecules can be generated Amber Webster, www.amberlwebster.com.

12 April 2017

Congratulations to Teerawut Bootwicha, Julian Feilner, Eddie Myers and Varinder Aggarwal who have published a paper in Nature Chemistry

Nature has evolved highly sophisticated machinery for organic synthesis. One of the most beautiful examples is its machinery for polyketide synthesis, a very important class of molecules, due to their broad spectrum of biological activities (eg. antibiotic, antitumor, antifungal, antiparasitic). In this process a simple thioester (small building block) is passed from one enzyme domain to another, growing as it does so until the target molecule is formed. The process resembles a molecular assembly line. We have sought to emulate Nature in the construction of our own molecular assembly line through a related iterative process. But iterative processes are very challenging as each iteration must occur with >99.5% efficiency, and >99.5% stereocontrol otherwise mixtures would result. Here we report a suite of reagents which reacts with our small building blocks (boronic esters) with exceptionally high fidelity and stereocontrol.

The reagents are capable of creating exactly the same functional groups found in the polyketide family of natural products: alternating hydroxyl and methyl groups. Through repeated iteration we have converted a simple building block into complex polyketide-like molecules with remarkably high precision over its length, and its stereochemistry. Indeed, the stereochemistry can essentially be dialled in at will simply by taking the appropriate reagent off the shelf.

This work should now enable one to rationally design and create polyketide-like molecules with novel biological properties to promote human health.

Further information

Paper
 
Authors: Teerawut Bootwicha, Julian M. Feilner, Eddie L. Myers & Varinder K. Aggarwal
 
Nature Chemistry (2017) doi:10.1038/nchem.2757
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