Expanding Sulfonamide Chemistry
A new synthetic method developed in York that enables the simple synthesis of a wide range of biologically important cyclic sulfur-containing molecules has been discovered.
These molecules – known as ‘sulfonamides’ – are common components found in small molecule drugs, used to treat cancer, HIV and various viral and bacterial infectious diseases. Molecules arranged in large rings – also known as ‘macrocycles’ – are also very important compounds in medicines. However, synthetic methods able to install sulfonamide groups into macrocycles are scarce, thus limiting the ability to use this potentially valuable combination to discover new treatments for disease.
Dr Will Unsworth and his research team have great interest in the development of new and improved synthetic routes to macrocycles and set out to use their expertise to make macrocyclic sulfonamides.
They combined two distinct synthetic strategies, both of which are based on cascade reactions – processes which combine multiple reaction steps into a single operation (see Figure). Cascade reactions bring several benefits in terms of making synthesis quick and easy, and avoiding the need to handle or isolate potentially toxic intermediates. The team made use of nitro groups or alkenes as masked amines that could be unmasked via reduction or conjugate addition respectively. This allows a diverse range of componds to be simply and efficiently turned into cyclic sulfonamides. These two new reactions allow access to families of previous inaccessible molecules, enabling their biological potential to be properly explored.
The teamwork on this project exemplifies the collaborative and international ethos in much of the research carried out in the Department of Chemistry at the University of York. The work to develop one of the two new synthetic methods was led by Chinese PhD Zhongzhen Yang. The second was led by Ukrainian PhD student Illya Zalessky, who deserves huge credit for driving this research whilst also working to support refugees escaping the war in his homeland. The project was also supported by predictive computational chemistry, conducted by PhD student Ryan Epton and Prof Jason Lynam.
Speaking about the research Dr Unsworth said: “Although we have worked on ring expansion reaction, we have never explored sulfonamides before. With the discovery of these two new reaction classes, we can now make macrocyclic sulfonamides remarkably easily, which will enable the exploration of their pharmaceutical properties.’
The research is published in Angewandte Chemie