Three-dimensional molecular scaffolds, such as spirocyclic compounds, provide an avenue to depart from the extensively explored aromatic molecular “flatlands”.
Your entry into spirocycles constructed from ring sizes outside the more common five- and six-membered, or of increased chemical complexity, is our drive for the discovery of new chemical methodology. A recent cheminformatics approach in collaboration with researchers from the University of Bonn, Germany, resulted in the development and improvement of synthetic methods to spirocyclic compounds:
Spirocyclic morpholine scaffolds became readily available on a gram scale by a prins cascade cyclization as mixtures of diastereoisomers. Analytical method development led to the efficient separation of the isomers by supercritical fluid chromatography and structure determination by x-ray crystallography and 2d nmr spectroscopy.
Spiro-oxindoles were synthesized by lewis acid promoted prins cyclization. The available building blocks are easily accessible, and the reaction works with aromatic and aliphatic aldehydes.
The synthesis of an interesting natural product tetracyclic core was achieved, but the compound was unstable in follow-up chemistry. A detailed investigation resulted in a tert-butyloxycarbonyl (boc) protection strategy that made large-scale preparation and handling possible. The material can now be used in library chemistry.
These are just three examples of how discovery chemists push the development of new chemical entities further!