Stereocontrolled organocatalytic synthesis of prostaglandin PGF2α in seven steps.
Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made prostaglandins popular targets for synthetic organic chemists for over 40 years. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma, 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, PGF2α, 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 groups. 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.
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK.
Graeme
G
Coulthard
William
W
Erb
Varinder K
VK
Aggarwal
D000447:Aldehydes / Q000737:chemistry; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic / Q000191:economics / Q000379:methods*; D015237:Dinoprost / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D011392:Proline / Q000737:chemistry; D011461:Prostaglandins F, Synthetic / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
D000447:Aldehydes; D011461:Prostaglandins F, Synthetic; C116609:3-hydroxybutanal; D011392:Proline; D015237:Dinoprost