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Stereocontrolled organocatalytic synthesis of prostaglandin PGF in seven steps

Abstract

Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction1,2. Their biological activities and their complex molecular architectures have made prostaglandins popular targets for synthetic organic chemists for over 40 years3,4. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma5,6, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex prostaglandin, PGF, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups7. Access to this bicyclic enal will not only render existing prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic prostaglandin analogues.

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Figure 1: Prostaglandins in nature and medicine.
Figure 2: Potential reaction pathways of the proline-catalysed aldol reaction of succinaldehyde.
Figure 3: Model studies.
Figure 4: A concise asymmetric synthesis of PGF

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Acknowledgements

We thank EPSRC and the European Research Council (FP7/2007-2013, ERC grant no. 246785) for financial support. V.K.A. thanks the Royal Society for a Wolfson Research Merit Award and EPSRC for a Senior Research Fellowship.

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Authors and Affiliations

Authors

Contributions

G.C. and W.E. were involved in the discovery and subsequent development of the aldol reaction and G.C. applied it to PGF. V.K.A. conceived and directed the investigations and composed the manuscript with revisions provided by G.C. and W.E.

Corresponding author

Correspondence to Varinder K. Aggarwal.

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The authors declare no competing financial interests.

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Coulthard, G., Erb, W. & Aggarwal, V. Stereocontrolled organocatalytic synthesis of prostaglandin PGF in seven steps. Nature 489, 278–281 (2012). https://doi.org/10.1038/nature11411

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