Modelling of Lewis-Acid Catalyzed Ring Opening of Oxanorbornenes in the Synthesis of Azaheterocyclic Phosphonates

Since the discovery of the biological activity of aminophosphonates, research started on the synthesis of more constraint azaheterocyclic phosphonates. We developed a route via an intramolecular Diels-Alder reaction towards α-aminophosphonates 1. The obtained oxanorbornene skeleton is a valuable synthetic intermediate that has been used in various natural product syntheses. An important synthetic transformation involves the cleavage of the oxygen bridge, used to construct substituted arenes and cyclohexenes. We wanted to investigate the ring opening of adducts 1 using different Lewis acids experimentally and to get more insight in the reaction pathways towards the different products via molecular modelling. In this presentation the results obtained with TiCl4 and FeCl3 catalyst are shown. One of the difficulties in studying transition metal catalysts is the determination of their proper spin state. The tetrahedral TiCl4 monomer has spin zero. The FeCl3 catalyst has a high-spin ground state. It prefers a half-filled d-shell and has multiplicity 6. The complexation of the Lewis acids with different binding sites was investigated at a B3LYP level of theory with a LanL2DZ pseudopotential for the transition metals. Bidentate coordination towards the most electronegative phosphonate oxygen and the oxygen bridge is favoured for both catalysts. The reaction pathways were evaluated at a TPSSh and a B3LYP level of theory. The role of dispersion interactions was evaluated using the Van der Waals correction term from B3LYP-D. The energy barrier for breaking the C-O bond with FeCl3 is larger than with TiCl4. This corresponds with the experimental observation that the titanium catalyzed reaction completes at 0°C and the reaction with the iron catalyst requires reflux conditions in CH2Cl2. The main difference between the TiCl4 and FeCl3 as Lewis acids in the opening of the oxanorbornene oxygen bridge is their way of stabilizing the oxide anion. When the C-O bond is broken, the bond between the alkoxide anion and the transition metal tightens. With TiCl4, the alkoxide replaces a chloride that adds to the allyl cation in a concerted way. With FeCl3, however, the carbocation is stabilized by the alkoxide anion itself and no chloride transfer occurs; instead, the bond with the phosphonate is broken. A plausible further reaction path towards the experimentally observed ketone involves a 1,2-hydride shift

Cleavage of the Oxanorbornene Oxygen Bridge with Lewis Acids: Computation and Experiment

Since the discovery of the biological activity of aminophosphonates, research started on the synthesis of more constraint azaheterocyclic phosphonates. We developed a route via an intramolecular Diels-Alder reaction towards α-aminophosphonates 1. [1] The obtained oxanorbornene skeleton is a valuable synthetic intermediate that has been used in various natural product syntheses. [2] An important synthetic transformation involves the cleavage of the oxygen bridge, used to construct substituted arenes and cyclohexenes. We wanted to investigate the ring opening of adducts 1 using different Lewis acids experimentally and get more insight in the reaction pathways towards the different products via computational experiments. In this presentation the results obtained with TiCl4 and FeCl3 catalyst are shown. The computational study started with the catalysts and their multiplicity. Next, the complexation energy with different binding sites was calculated. Therefore, a level of theory study was done using an ONIOM QM/QM approach. This shows the importance of the inclusion of electron correlation effects. B3LYP geometries and energies can be used as a good approximation. Bidentate coordination towards the most electronegative phosphonate oxygen and the oxygen bridge is favoured for both catalysts. Then, different reaction pathways were investigated via a static, gas-phase approach. The energy barrier towards the transition state using the TiCl4 catalyst, shown in Figure 1, is much lower than for the FeCl3 catalyst and very different products are formed. The computational results were compared with the experiments

A combined experimental and theoretical investigation of the stereoselectivity in the synthesis of azahetrocyclic phosphonates

Since the discovery of the biological activity of aminoalkylphosphonates, e.g. as enzyme inhibitors, many researchers have focused their attention on conformationally constrained azaheterocyclic phosphonates. Stereocontrol is of major interest during the synthesis of these products. Therefore our research group has developed a new route towards tricyclic phosphono pyrrolidines using an intramolecular Diels-Alder reaction with furans (IMDAF), as given in the scheme. We wanted to reveal the stereoselectivity of these IMDAF-reactions experimentally and computationally. This would enable us to direct the reaction to one isomer and gives an idea of the influence of the position of the carbonyl group on the stereoselectivity. 2OP(OMe)2N1ONP(OMe)2OOROOROP(OMe)2NR3O4RNP(OMe)2OOOO Difference NOE, 2-dimensional NMR-data and an X-ray analysis of adducts 2 revealed that the cycloaddition occurred exo, but the phosphonate substituent on the tether had an exo- or endo-orientation. A thermodynamic preference for the minor isomer with an endo-substituent was observed experimentally. DFT calculations confirmed this and linked it with a larger steric hindrance of the bulky tether substituents in the exo-isomer. The same computational methods predicted that the single isomer formed starting from aminophosphonate 3 was the endo-isomer. A relation with the JHP coupling constant was found. Furthermore, a computational study at the post Hartree-Fock level could reproduce the kinetic preference for the exo-isomer of adduct 2, while the presence of the carbonyl function in the tether results in the endo-isomer only

Combination of experimental and computational chemistry in the synthesis of new azahetrocycles

This PhD was planned as a combination of experimental and computational chemistry. The goal was to synthesize new azaheterocyclic compounds with an interesting potential for biological activity starting from pyroglutamates and α-aminophosphonates, as the SynBioC research group has a lot of experience with these compounds, and to investigate different ways of conformational restriction via cyclization. The use of the computational methods to explain observed isomer ratios, stereoselectivities and reactivities, is supposed to bring insights that improve the chemical intuition. Meanwhile the applicability of the methods is evaluated and its use in a predictive way for similar reactions, can lead to the final goal of computational chemistry, i.e. to have predictive power