Spirocyclic character of ixazomib citrate revealed by comprehensive XRD, NMR and DFT study

Abstract Ixazomib citrate is a very recently approved anti-cancer drug. Until now, to the best of our knowledge, no one has been able to solve any crystal structures of this compound. In this work, we present the crystal structures of two isostructural solvates of ixazomib citrate. In all currently available literature, the molecule is characterized as containing a single optically active carbon atom and a borate cycle formed when ixazomib is reacted with citric acid to form a stabilized ixazomib citrate that can be administered orally. However, the crystal structures revealed that none of the up-to-date presented structural formulas of ixazomib citrate are fully accurate. In addition to the citrate ring, another 5-membered ring is formed. These two rings are connected by the boron atom, making this compound a spirocyclic borate. By spirocyclization, the boron atom becomes tetrahedral and therefore optically active. In the crystal structures, ixazomib citrate was found to be in forms of two RR and RS stereoisomers. The results are supported by solid-state and solution NMR and DFT quantum mechanical calculations.