Experimental and computational study of the ring opening of tricyclic oxanorbornenes to polyhydro isoindole phosphonates

D.D. Claeys, C.V. Stevens, B.I. Roman, P. Van De Caveye, M. Waroquier, V. Van Speybroeck
Organic & Biomolecular Chemistry
8, 3644-3654


Phosphonylated azaheterocycles are an important class of compounds with high biological potential as conformationally restricted bioisosteres of amino acids. Therefore, it is of interest to synthesize conformationally constrained amino phosphonates. We wanted to investigate possible routes via ring opening of α-amino phosphonates with an oxanorbornene skeleton, as these can be synthesized with high stereoselectivity. This was achieved using different Lewis acids, leading to a range of products. The reaction with TiCl4 and FeCl3 was modelled at a DFT level of theory to get insight in the pathways towards the corresponding products. To ease the work up, the Fe(III) catalyst was coated on montmorillonite clay, but this accelerated aromatization after ring opening. Quenching the FeCl3 catalyzed reaction mixture on celite caused complete aromatization.