Diels Alder reaction stitches up macrocycles


Organic chemists in the US have developed a method to control the stereochemistry of a useful intramolecular Diels-Alder reaction.

Led by Eric Jacobsen at Harvard University, Massachusetts, the team used catalysts to perform transannular Diels-Alder reactions with good yield and chiral control. This research provides synthetic chemists with an alternative pathway to developing complex drugs and natural products. 

The Diels-Alder is an important reaction in the organic chemist’s toolbox, allowing a six-membered ring to be generated from a conjugated diene and dienophile. This reaction can be used to introduce ring systems into a molecule, such as in a ’transannular’ reaction - where a large ring system is stitched up across the centre, creating at least three rings in a single step.

Transannular Diels-Alder reactions have been key processes in many natural product syntheses and give rise to multiple chiral centres. Controlling the stereochemistry at these centres has proven difficult, but it is important to do so because many interesting molecules require specific chirality in the final product.   

Jacobsen’s team tested a series of macrocycles using catalysts based on an oxazaborolidine structure that was developed by E J Corey (see image).These catalysts are straightforward to prepare and contain a Lewis-acidic centre that coordinates to the dienophile, activating it to encourage reaction. 


The oxazaborolidine catalyst left the macrocycle all stitched up

© Science

The breakthrough came when a fluorinated aromatic group was introduced into the catalyst structure and the team were able to produce multi-ringed products with excellent enantioselectivity, diastereoselectivity and yield. 

The team demonstrated the versatility of the technique by forming seven- and eight-membered rings, and using different dienophiles. Emily Balskus, who worked on the project, told Chemistry World: ’For achiral macrocycles, this methodology offers a means of controlling absolute stereochemistry that did not exist until now. Ideally this reaction will inspire synthetic chemists to pursue targets they might not have otherwise undertaken.’

Richard Brown, an expert on natural product synthesis at the University of Southampton, commented: ’Being able to quickly generate complexity in molecules is key to building complicated targets. But controlling the stereochemistry is a fundamental aspect of this, and the more methods we have to do so, the better.’ 

Lewis Brindley