π-Facial selectivity in the Diels–Alder reaction of glucosamine-based chiral furans and maleimides

My name is Kees van der Loo. I’m working to obtain my PhD degree at Symeres, in collaboration with the University of Groningen. In my research, I study the use of biorenewable carbohydrates as a sustainable starting material for library synthesis.

The goal of the project is to find innovative ways to access novel scaffolds that can be used to synthesize biologically relevant compound libraries. Dehydration of glucosamine derivatives affords enantiopure chiral furanic building blocks with a substitution pattern that is not easily accessible synthetically. This makes them interesting starting points for the synthesis of a new class of stereochemically dense library scaffolds with a high degree of sp³-hybridized carbons.

In this project, Symeres is the industry partner that provides the laboratory facilities and contributes to the research with expertise in synthetic chemistry and knowledge on library scaffold synthesis.

The Diels–Alder study was started by Rutger Schim van der Loeff, an intern at the time and now employee at Symeres. After Rutger graduated, I continued the research, which ultimately led to the publication. At the end of the project, the team got a more international feel, as a collaboration was started with the University of Alcala (Spain) to assist with X-ray crystallography.

Several analytical and synthetic hurdles needed to be overcome. In a single reaction, two relatively simple molecules produce a mixture of four diastereomeric products with complex three-dimensional structures and four new chiral centers. Due to the structural complexity and similarity of the products, both analysis and purification had interesting challenges. Reaction monitoring by ¹H NMR spectroscopy was hampered by signal overlap in the NMR spectrum. This was solved by a preanalysis Malaprade oxidation step to remove the interfering structural moiety, which made the diagnostic proton signals visible. Purification challenges were overcome by combining column chromatography with a postpurification aqueous wash to suppress degradation during isolation of the product. Ultimately, the product was synthesized on a multigram scale in nearly 60% yield and >99% diastereomeric excess.

A scaffold was prepared with a total of five new chiral centers, and we needed to resolve the absolute stereoconfiguration. Based on a comprehensive NMR study, we narrowed the possibilities down to two plausible configurations. However, for conclusive proof, we had to resort to X-ray crystallography. Unfortunately, none of the intermediates were crystalline, and therefore, several derivatives were prepared. Eventually, we found a crystalline derivative, and we collaborated with the University of Alcala to obtain the crystal structure (figure 2), which brought the project to a very satisfying end.